Amide linker peroxisome proliferator activated receptor modulators

ABSTRACT

The present invention is directed to compounds, compositions, and use of compounds the structural Formula (I)

This Application claims the benefit of U.S. Provisional Application Ser.No. 60/390,102, filed Jun. 19, 2002, and PCT Application Ser. No.PCT/US03/16207, filed Jun. 11, 2003.

BACKGROUND OF THE INVENTION

Peroxisome Proliferator Activated Receptors (PPARs) are members of thenuclear hormone receptor super family, which are ligand-activatedtranscription factors regulating gene expression. Various subtypes ofPPARs have been discovered. These include, for example, PPARα, NUC1,PPARγ and PPARδ.

PPARα, PPARγ and PPARδ receptors have been implicated in diabetesmellitus, cardiovascular disease, obesity, Syndrome X andgastrointestinal disease, such as, inflammatory bowel disease. SyndromeX is the combination of symptoms which include hyperinsulemia combinedwith hypertension, elevated body weight, elevated triglycerides andelevated LDL.

Current PPAR agonist treatment for Syndrome X relates to the use ofthiazolidinediones (TZDs) or other insulin sensitivity enhancers (ISEs).TZDs are a class of PPAR gamma agonists that have been shown to increasethe sensitivity of insulin sensitive cells. Increasing insulinsensitivity rather than the amount of insulin in the blood reduces thelikelihood of hypoglycemic coma. However, TZDs and ISEs have beenassociated undesirable clinical effects and improved clinical profilesare desired. Therefore, a need exists for new pharmaceutical agentshaving a desirable pharmacological profile. Such PPAR selective or dualselective agonist compounds are especially desirable when associatedwith a desirable safety profile and the desired effect in the treatmentof diabetes and/or related clinical conditions.

SUMMARY OF THE INVENTION

An embodiment of the present invention is directed toward compoundsrepresented by the structural formula I:

(a) R1 is selected from the group consisting of hydrogen, C₁-C₈ alkyl,C₃-C₆ cycloalkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl,aminoC₁-C₄alkyl, C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, arylheteroC₁-C₈alkyl,—CHC(O)C₁-C₄ alkoxy, C₀₋₄-alkyl-C(O)heteroC₁-C₈alkyl, and—CH₂—C(O)—R15-R16; and which C₁-C₈ alkyl, C₃-C₆ cycloalkyl,aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, aminoC₁-C₄alkyl, C₃-C₆cycloalkylaryl-C₀₋₂-alkyl, arylheteroC₁-C₈alkyl, —CHC(O)C₁-C₄ alkoxy,C₀₋₄-alkyl-C(O)heteroC₁-C₈alkyl and —CH₂—C(O)—R15-R16 are eachindependently unsubstituted or substituted with from one to threesubstituents each independently selected from the group consisting ofR1′; and wherein R15 is O or NH and R16 is C₁-C₂ alkyl or benzyl, whichC₁-C₂ alkyl or benzyl are each unsubstituted or substituted with fromone to three substituents each independently selected from the groupconsisting of R16′;

(b) R1′ and R2′ are each independently a group consisting of C₁-C₅alkyl, C₃-C₆ cycloalkyl, C₁-C₅ alkoxy, arylC₀-C₂alkoxy, haloC₁-C₃alkyl,halo, aryl, —C(O)C₁-C₅alkyl, —C(O)-aryl, haloC₁-C₅alkyloxy,arylC₁-C₅alkyl, and biarylC₁-C₅alkyl; and which —C(O)-aryl isunsubstituted or substituted with from one to three substituents eachindependently selected from the group consisting of halo, C₁-C₅ alkyl,haloC₁-C₅ alkyl, C₁-C₅ alkoxy, and —C(O)C₁-C₅alkyl; and which C₁-C₅alkyl, arylC₁-C₅alkyl, biarylC₁-C₅alkyl, and aryl are each independentlyunsubstituted or substituted with from one to three substituents eachindependently selected from the group consisting of halo, C₁-C₈alkyl,aryl, haloC₁-C₅ alkyl, trihaloC₁-C₃alkyl, C₁-C₅alkoxy, andarylC₁-C₅alkyl; and which aryl is unsubstituted or substituted with fromone to three substituents each independently selected from the groupconsisting of halo, C₁-C₈alkyl, aryl, haloC₁-C₅alkyl, trihaloC₁-C₃alkyl,C₁-C₅alkoxy, and arylC₁-C₅alkyl;

(c) R2 is selected from the group consisting of C₁-C₈ alkyl, C₃-C₆cycloalkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, hetoC₁-C₆cycloalkylaryl, hetoC₁-C₆cycloalkylarylC₁-C₄alkyl, aminonoC₁-C₄alkyl,C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, arylheteroC₁-C₈alkyl,C₀₋₄-alkyl-C(O)heteroC₁-C₈alkyl, —CH(C(O)OCH₃)benzyl, and—CH₂—C(O)—R15″-R16″, and which C₁-C₈ alkyl, C₃-C₆ cycloalkyl,aryl-C₀₋₄-alkyl, hetoC₁-C₆cycloalkylaryl,hetoC₁-C₆cycloalkylarylC₁-C₄alkyl, heteroaryl-C₀₋₄-alkyl,aminoC₁-C₄alkyl, C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, arylheteroC₁-C₈alkyl,C₀₋₄-alkyl-C(O)heteroC₁-C₈alkyl, and —CH₂—C(O)—R15″-R16″ are eachindependently unsubstituted or substituted with from one to threesubstituents each independently selected from the group consisting ofR2′;

(d) R15″ is O or NH;

(e) R16″ is C₁-C₂ alkyl or benzyl which C₁-C₂ alkyl and benzyl are eachunsubstituted or substituted with from one to three substituents eachindependently selected from the group consisting of R16′;

(f) R1 and R2 together may form a heterocyclic ring which heterocyclicring is unsubstituted or substituted with from one to three substituentseach independently selected from the group consisting of R1′ and whichheterocyclic ring is optionally fused with an aryl;

(g) E is selected from the group consisting of C(R3)(R4)A, (CH₂)_(n)COOR13, aryl-C₀₋₄-alkyl, thio-C₁-C₄-alkyl, thioaryl, arylC₁-C₄alkoxy,C₁-C₄alkoxy C₁-C₄alkyl, aminoaryl, and amino C₁-C₄alkyl; and which(CH₂)_(n) COOR13, aryl-C₀₋₄-alkyl, thio-C₁-C₄-alkyl, thioaryl,C₁-C₄alkoxyaryl, C₁-C₄alkoxyC₁-C₄alkyl, aminoaryl, and aminoC₁₋₄alkylare each independently unsubstituted or substituted with from one tothree substituents each independently selected from the group consistingof E′;

(h) R7′ and R7″ are each independently selected from the groupconsisting of C₁-C₄ alkyl and C₁-C₄ haloalkyl;

(i) n and m are each independently selected from the group consisting of0, 1, 2 and 3;

(j) A is selected from the group consisting of (CH₂)_(m) COOR14,C₁-C₃alkylnitrile, carboxamide, sulfonamide, acylsulfonamide andtetrazole, and which sulfonamide, acylsulfonamide and tetrazole are eachindependently unsubstituted or substituted with from one to threesubstituents each independently selected from the group consisting ofA′;

(k) A′ is a group consisting of C₁-C₄alkyl, C₁-C₄ haloalkyl, heteroaryl,and aryl, and wherein heteroaryl and aryl are each independentlyunsubstituted or substituted with from one to three substituents eachindependently selected from the group consisting of halo, C₁-C₅ alkyl,C₁-C₅ haloalkyl, C₁-C₅ alkoxy, and —C(O)C₁-C₅ alkyl;

(l) R3 is selected from the group consisting of H, C₁-C₅ alkyl, C₁-C₅alkenyl, and C₁-C₆ alkoxy;

(m) R4 is selected from the group consisting of H, halo, C₁-C₅ alkyl,C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryl C₀-C₄ alkyl, and C₀₋₄alkoxyaryl,and which C₁-C₅ alkyl, C₁-C₅ alkoxy, C₃-C₆ cycloalkyl, aryl C₀-C₄ alkyl,and C₀₋₄alkoxyaryl are each independently unsubstituted or eachindependently substituted with from one to four substituents eachindependently selected from R4′; or R3 and R4 are combined to form aC₃-C₆ cycloalkyl;

(n) R5 and R6 are each independently selected from the group consistingof hydrogen, C₁-C₈ alkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, C₃-C₆cycloalkylaryl-C₀₋₂-alkyl, C₃-C₆ cycloalkyl-C₀₋₂-alkyl, and—CH₂—C(O)—R17-R18, and which C₁-C₈ alkyl, aryl-C₀₋₄-alkyl,heteroaryl-C₀₋₄-alkyl, C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, C₃-C₆cycloalkyl-C₀₋₂-alkyl; and —CH₂—C(O)—R17-R18 are each independentlyunsubstituted or substituted with from one to four substituents eachindependently selected from the group consisting of R5′;

(o) E′, R4′, R5′, and R13″ are each independently a group consisting ofC1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C1-C5 haloalkoxy, nitro,cyano, CHO, hydroxy, C₁-C₄ alkanoic acid, phenyl, aryloxy, SO₂R7′, SR7″,arylC₀-C₂alkoxy, C1-C6alkylcarboxamido, and COOH;

(p) R16′ is a group consisting of halo, C₁-C₈alkyl, aryl, haloalkyl,trihaloC₁-C₃alkyl, C₁-C₅alkoxy, and arylC₁-C₅alkyl;

(q) R17 and R18 are each independently selected from C₁-C₈ alkyl,aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl,and C₃-C₆ cycloalkyl-C₀₋₂-alkyl;

(r) R13 and R14 are each independently selected from the groupconsisting of hydrogen, C1-C4alkyl, aryl, and arylmethyl, and whichC1-C4alkyl are each independently unsubstituted or independentlysubstituted with from one to three substituents each independentlyselected from the group consisting of R13′ and which arylmethyl and arylare each independently unsubstituted or independently substituted withfrom one to three substituents each independently selected from thegroup consisting of R14′;

(s) R13′ is a group consisting of C₁-C₅ alkyl, C₃-C₆ cycloalkyl, C₁-C₅haloalkyl, C₁-C₅ alkoxy, aryloxy, halo, aryl, —C(O)C₁-C₅alkyl,—C(O)-aryl, haloC₁-C₅alkyloxy, aryl C₁-C₅ alkyl, and C₁-C₅ alkylbiaryl,and which —C(O)aryl, aryl, aryl C₁-C₅ alkyl, and C₁-C₅ alkylbiaryl areeach independently unsubstituted or substutited with from one to threesubstituents each independently selected from the group consisting ofR13″; and

(t) R14′ is a group consisting of halo, C1-C8alkyl, C₁-C₅ haloalkyl,C₁-C₅ alkoxy, and arylC₀-C₄alkyl; or

(u) a pharmaceutically acceptable salt thereof.

An embodiment of the present invention is directed toward compoundsrepresented by the following structural formula:

(a) R1 is selected from the group consisting of hydrogen, C₁-C₈ alkyl,C₃-C₆ cycloalkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl,aminoC₁-C₄alkyl, C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, arylheteroC₁-C₈alkyl,—CHC(O)C₁-C₄ alkoxy; C₀₋₄-alkyl-C(O)heteroC₁-C₈alkyl, and—CH₂—C(O)—R15-R16; wherein said C₁-C₈ alkyl, C₃-C₆cycloalkyl,aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, aminoC₁-C₄alkyl, C₃-C₆cycloalkylaryl-C₀₋₂-alkyl, arylheteroC₁-C₈alkyl, —CHC(O)C₁-C₄ alkoxy,C₀₋₄-alkyl-C(O)heteroC₁-C₈alkyl, and —CH₂—C(O)—R15-R16 are eachindependently optionally substituted with from one to three substituentseach independently selected from the group consisting of R1′; whereinR15 is O or NH and R16 is benzyl optionally substituted with from one tothree substituents each independently selected from the group consistingof R16′;

(b) R2 is selected from the group consisting of C₁-C₈ alkyl, C₃-C₆cycloalkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, aminoC₁-C₄alkyl,C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, arylheteroC₁-C₈alkyl,C₀₋₄-alkyl-C(O)heteroC₁-C₈alkyl, and —CH₂—C(O)—R¹⁵-R¹⁶; wherein saidC₁-C₈ alkyl, C₃-C₆ cycloalkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl,aminoC₁-C₄alkyl, C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, arylheteroC₁-C₈alkyl,C₀₋₄-alkyl-C(O)heteroC₁-C₈alkyl, and —CH₂—C(O)—R¹⁵-R¹⁶ are eachindependently optionally substituted with from one to three substituentseach independently selected from the group consisting of R2′; whereinR¹⁵ is O or NH and R¹⁶ is benzyl optionally substituted with from one tothree substituents each independently selected from the group consistingof R16″;

(c) R1 and R2 together may form a substituted or unsubstitutedheterocyclic ring;

(d) E is selected from the group consisting of C(R3)(R4)A, and asubstituted or unsubstituted selected from the group consisting of(CH₂)_(n) COOR13, aryl-C₀₋₄-alkyl, thio-C₁₋₄-alkyl, thioaryl,C₁₋₄alkoxyaryl, C₁₋₄alkoxyC₁₋₄alkyl, aminoaryl, and aminoC₁₋₄alkyl;

(e) n and m are each independently selected from the group consisting of0, 1, 2 and 3;

(f) A is an functional group selected from the group consisting of(CH₂)_(m) COOR14, C₁-C₃alkylnitrile, carboxamide, substituted orunsubstituted sulfonamide, substituted or unsubstituted acylsulfonamideand substituted or unsubstituted tetrazole;

(g) R3 is H, saturated or unsaturated C₁-C₅ alkyl, C₁-C₅ alkoxy;

(h) R4 is H, halo, a substituted or unsubstituted group selected fromC₁-C_(5 alkyl, C) ₁-C₅ alkoxy, C₃-C₆ cycloalkyl, aryl C₀-C₄ alkyl,C₁₋₄alkoxyaryl, and phenyl, or R3 and R4 are combined to form a C₃-C₆cycloalkyl;

(i) R5 and R6 are each independently selected from the group consistingof hydrogen, substituted or unsubstituted group selected from C₁-C₈alkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, C₃-C₆cycloalkylaryl-C₀₋₂-alkyl, C₃-C₆ cycloalkyl-C₀₋₂-alkyl, and—CH₂—C(O)—R17-R18;

(j) R17 and R18 are each independently selected from C₁-C₈ alkyl,aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl,and C₃-C₆ cycloalkyl-C₀₋₂-alkyl;

(k) R13 and R14 are each independently selected from the groupconsisting of hydrogen, optionally substituted C1-C4alkyl and optionallysubstituted arylmethyl; and pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a compound of Formula II:

wherein R19 is selected from the group consisting of hydrogen,C1-C4alkyl, aryl, and arylmethyl, wherein the alkyl, aryl and arylmethylis unsubstituted or substituted with from one to three substituents eachindependently selected from R14′;and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4,R5, and R6 are as as defined above in Formula I.

Another embodiment of the present invention is a compound of FormulaIII:

wherein R19 is selected from the group consisting of hydrogen, whereinR19 is selected from the group consisting of hydrogen, C1-C4alkyl, aryl,and arylmethyl, wherein the alkyl, aryl and arylmethyl is unsubstitutedor substituted with from one to three substituents each independentlyselected from R14′.;and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4,R5, and R6 are as defined above in Formula I.

Another embodiment of this invention is a compound and pharmaceuticallyacceptable salts of Structural Formula:

wherein R11 is selected from the group consisting of aryl, aryloxy,—C(O)aryl, haloC₁-C₅alkyloxy, C₁-C₅ alkylaryl, C₁-C₅ alkylbiaryl, andC1-C6 alkyl, wherein the aryl, —C(O)aryl, haloC₁-C₅alkyloxy, C₁-C₅alkylaryl, C₁-C₅ alkylbiaryl, and C1-C6 alkyl are each independentlyunsubstituted or each independently substituted with from one to threesubstituents each independently selected from the group consisting ofR1′.

Another preferred embodiment is a compound and pharmaceuticallyacceptable salts of Structural Formula:

wherein R12 is selected from the group consisting of aryl, aryloxy,—C(O)aryl, haloC₁-C₅alkyloxy, arylC₁-C₅ alkyl, C₁-C₅ alkylbiaryl, andC1-C6 alkyl, wherein the aryl, —C(O)aryl, aryloxy, haloC₁-C₅alkyloxy,C₁-C₅ alkylaryl, C₁-C₅ alkylbiaryl, and C1-C6 alkyl are eachindependently unsubstituted or each independently substituted with fromone to three substituents each independently selected from the groupconsisting of R1′.

Another embodiment is a compound of the formula:

In another feature of this invention, a compound claimed herein isradiolabeled.

In one embodiment, the present invention also relates to pharmaceuticalcompositions which comprising at least one compound of the presentinvention, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

In another embodiment, the present invention relates to a method ofmodulating a PPAR alpha receptor by contacting the receptor with atleast one compound represented by Structural Formula I, and/orpharmaceutically acceptable salts thereof.

In another embodiment, the present invention relates to a method ofmodulating a PPAR gamma receptor by contacting the receptor with atleast one compound represented by Structural Formula I, and/orpharmaceutically acceptable salts thereof.

In another embodiment, the present invention relates to a method ofmodulating a PPAR delta receptor by contacting the receptor with atleast one compound represented by Structural Formula I, and/or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to a method ofmodulating a PPAR alpha receptor and a PPAR gamma receptor by contactingthe receptor with at least one compound represented by StructuralFormula I, and/or pharmaceutically acceptable salts thereof.

In another embodiment, the present invention relates to a method ofmodulating a PPAR gamma and a PPAR delta receptor by contacting thereceptor with at least one compound represented by Structural Formula I,and/or a pharmaceutically acceptable salt there of.

The compounds of the present invention can be effective in treating and,in patients susceptible thereto, preventing, Syndrome X, Type IIdiabetes, hyperglycemia, hyperlipidemia, obesity, coagaulopathy,hypertension, atherosclerosis, and other disorders related to Syndrome Xand cardiovascular diseases. In addition, the compounds are expected tobe associated with more favorable clinical safety and efficacy profilethan compounds currently used to treat these conditions. Further,compounds of this invention can be useful for lowering fibrinogen,increasing HDL levels, treating renal disease, controlling desirableweight, treating demyelinating diseases, treating certain viralinfections, and treating liver disease.

DETAILED DESCRIPTION OF THE INVENTION

The terms used to describe the instant invention have the followingmeanings herein.

As used herein, “alkyl” groups include straight chained and/or branchedhydrocarbons, which are completely saturated. Thus, such alkyl may beselected from primary, secondary, tertiary and the like. The term“C₀-C_(n′) alkyl” means an alkyl group having the stated number ofcarbon atoms. A preferable C₀-C_(n′) alkyl is methyl, ethyl, propyl, orbutyl in one preferred embodiment of the present invention. Anotherpreferred C1-C4 alkyl is methyl or ethyl.

As used herein, the term “aminoC1-C4alkyl” means that the amino group islinked to the base molecule through an alkyl having the stated number ofcarbon atoms.

The term “—C(O)alkyl” means that the alkyl, having the stated number ofcarbon atoms, is linked to the base molecule through a “—C(O)—” linker.Likewise, —C(O)C1-C5alkyl means an alkyl having from one to five carbonatoms linked to the base molecule via a —C(O) linker.

As used herein, “alkylene” is an unsaturated C₁-C₅ straight or branchedchain hydrocarbon group having at least one double bond.

“Cycloalkyl” groups, and “C₃-C₆ cycloalkyl” as used herein, includecyclic hydrocarbons having the stated number of carbon atoms in thering, which are partially or completely saturated. It can be preferredthat the cycloalkyl groups are completely saturated. It may be preferredthat cyclo alkyl is a ring having C₃-C₇ alkyl in the ring. Suchcycloalkyl includes, but is not limited to cyclpropyl, cyclopentyl,cyclohexyl, and the like.

As used herein, “aryl” groups include carbocyclic aromatic ring systems(e.g. phenyl), fused polycyclic aromatic ring systems (e.g. naphthyl andanthracenyl) and aromatic ring systems fused to carbocyclic non-aromaticring systems (e.g., 1,2,3,4-tetrahydronaphthyl and benzodioxyl). Apreferred aryl group can be phenyl. Another preferred aryl can benaphthyl. As used herein, “arylalkyl” means that the aryl group islinked to the point of attachment through an alkyl linker having thestated number of carbon atoms. It may be preferred that the alkyl isC0-C3 or C1-C3 alkyl. The term “aryl-C₀alkyl” means that the aryl groupis directly linked at the point of attachment through a bond. As usedherein, the term “alkylaryl” and “C1-C5 alkylaryl” also mean that thearyl is linked to the point of attachment though an alkyl linker havingthe stated number of carbon atoms and said alkyl linker is straightchain or branched. Additionally, said linker and/or aryl can besubstituted when said substituent is “substituted”. It can be preferredthat the alkyl linker is from one to three carbon atoms. A preferredaryl may be a C6-C10 aryl. The term “arylmethyl” means an arylalkyl thatis arylC₁alkyl.

As used herein the term “aryl substituent” has the same meaning as“aryl” as defined herein above. The term “—C(O)aryl substituent” meansthat the aryl group is linked to the base molecule through a —C(O)—linker. Further, as used herein, the term “—C(O)aryl” has the samemeaning as “—C(O)aryl substituent”.

As used herein, the term “aryloxy” means that an aryl group is linked tothe base molecule through an oxygen. The term “arylC₀-C₂ alkoxy” meansthat the arylalkyl is linked to the base molecule through an oxygen.When arylC₀-C₂alkoxy is arylC₀alkoxy, then the term means “aryloxy”.That is, the alkyl is absent when the term is aryl C₀alkoxy.

As used herein, the term “C1-C5alkylbiaryl” means an alkyl having thestated number of carbon atoms is linked to the base molecule and on theterminal end of said alkyl, is substituted with two independent arylgroups. In one preferred embodiment, it is preferred that each of thearyl of the biaryl is phenyl.

The term “cycloalkyaryl” means that a cycloalkyl group is fused with anaryl group to form a bicyclic substituent. Cycloalkylarylalkyl meansthat the fused bicyclic cycloalkylaryl is linked to the base moleculethrough an alkyl linker. That is “C3-C6 cycloalkylaryl-C0-C2alkyl” meansa cycloalkyl having from 3 to 6 carbon atoms is fused with an aryl andthen linked to the base molecule through an alkyl having from zero to 2carbon atoms. When there are zero carbon atoms, then the aryl is linkeddirectly to the base molecule.

The term “halo” means Cl, F, Br, and I. A preferred halo can be Cl.Another preferred halo can be F. As used herein the term “C1-C4haloalkyl” and “halo C1-C4alkyl” means the alkyl, having the statenumber of carbon atoms may be substituted with one or more halogens. Forexample, but not limited to, CF₃, C₂F₅, C₂F₃, C₃F₇, and the like.Likewise, the term “haloC1-C5alkyloxy” means an alkyl oxy having thestated number of carbon atoms substituted with one or more halogens. Thehaloalkyoxy is linked to the base molecule via the oxygen.

As used herein, “heteroaryl” groups include carbocyclic aromatic ringsystems wherein at least one carbon of the aryl group is replaced by atleast one independently selected heteroatom, such as nitrogen, oxygen orsulfur (e.g. pyridinyl and the like), fused polycyclic aromatic ringsystems having at least one heteroatom replacing a carbon from the ringand aromatic ring systems fused to carbocyclic non-aromatic ring systemshaving at least one heteroatom replacing a carbon atom from the ring. Apreferred heteroaryl may be C5-C10 heteroaryl. A preferred heteroarylgroup can be thiophenyl, pyridinyl, piperidinyl, pyrazinyl, and thelike. Another preferred heteroaryl group can be oxazole, thiazole, andthe like. Another preferred heteroaryl group can be thienyl, thiazole,benzothiazole, thiadiazole, and the like.

As used herein, the term “heteroaryl-C₀-C_(n′)alkyl” means that theheteroaryl is linked to the base molecule through an alkyl having thestated number of carbon atoms. As used herein, the term “heteroarylC₀alkyl” means that the heteroaryl is linked directed to the basemolecule.

As used herein, the term, “C₀₋₄-alkyl-C(O)heteroC₁-C₈alkyl” means thatthe heteroC₁-C₈alkyl group, wherein one of the carbon atoms of the alkylgroup is replaced with a heteroatom selected from the group consistingof S, O and N, is linked to the base nucleus through a C₀₋₄-alkylC(O)group. Embodiments include, but are not limited to when the heteroalkylis methoxy, ethoxy, propoxy, thiomethyl, thioethyl, thiopropyl,aminomethyl, aminoethyl, aminopropyl, and the like.

As used herein the term “C1-C5alkoxy” or “C1-Cn′ alkoxy” means that thealkyl having the stated number of carbon atoms is linked to the basemolecule through an oxygen.

As used herein the term “—CHC(O)C1-C4alkoxy” means that the alkoxyhaving the stated number of carbon atoms is linked to the base moleculethrough a —CH—C(O)-linker. Likewise, the term “—CH₂C(O)R15-R16” meansthat the R16 is linked to the base molecule through a “—CH₂C(O)R15”linker.

As used herein, the term, “arylheteroC₁-C₈alkyl” means that the arylgroup is attached to the base nucleus through a C₁-C₈alkyl group inwhich one of the carbon atoms of the alkyl group is replaced with aheteroatom selected from the group consisting of S, O, and N (herein“heteroalkyl linker”). One embodiment is when the heteroatom is an S andthe aryl is a phenyl which is unsubstituted or substituted with from oneto three substituents each independently selected from the groupconsisting of PHENYLSUB. Another embodiment is when the heteroatom is anO and the aryl is a phenyl which is unsubstituted or substituted withfrom one to three substituents each independently selected from thegroup consisting of PHENYLSUB. Another embodiment is an arylheteroalkylwherein aryl is unsubstituted or substituted with from one to threesubstituents each independently selected from PHENYLSUB and theheteroalkyl linker is unsubstituted or substituted with from one tothree substituents each independently selected from R1′ or R2′. Anotherembodiment is when the heteroatom is a N and the aryl is a phenyl whichis unsubstituted or substituted with from one to three substituents eachindependently selected from the group consisting of PHENYLSUB. Saidembodiments are in no way intended to limit the scope of the claimedinvention, and are provided to further illustrate a selection ofembodiments claimed herein. As used herein “PHENYLSUB” is a groupconsisting of halo, C1-C8alkyl, aryl, haloC₁-C₃alkyl, trihaloC1-C3alkyl,C₁-C₃ alkoxy, —C(O)C₁-C₄alkyl, and arylC₁-C₃alkyl.

“Heterocyclic group”, or “heterocyclic ring”, as used herein, is aC₃-C₁₂ ring system having the stated number of carbon atoms wherein fromone to three carbon atoms are replaced by a heteroatom such as nitrogen,sulfur or oxygen. Heterocyclic groups include benzofuranyl,benzothiazolyl, benzothienyl, isoquinolyl, isoxazolyl, morpholino,oxadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolyl, tetrahydropyranyland thienyl. It may be preferred that the heterocyclic ring is a threeto six membered the ring. Perferred heterocyclic rings may be

The term “heterocycloalkylaryl” means that a heterocyclic group, asdefined herein above, is fused to an aryl group to form the substituent.Such groups include, but are in no way limited to:

and the like. The term heterocycloaklylarylakyl means that theheterocycloalkylaryl is linked to the base molecule via an alkyl havingthe stated number of carbon atoms. Thus,hetoC₁-C₆cycloalkylarylC1-C4alkyl is a C1-C6 heterocyclic ring fusedwith an aryl and linked to the base molecule via a C1-C4 alkyl linker. Apreferred aryl can be phenyl.

The term “thioaryl” means that the aryl ring has at least one carbonatom replaced by a sulfur atom. Such thioaryl groups include, but arenot limited to thiophenyl, and the like.

The term “alkoxyaryl” mans that the aryl group is attached to the basemolecule through an alkoxy linker. The term “alkoxyalkyl” means that thealkyl chain has one carbon replaced by an oxygen atom. The term“aminoaryl” means that the aryl group is linked to the base moleculethrough an amino group. The term “aminoalkyl” means that the alkyl chainis attached to the base molecule through an amino group. The term“alkylnitrile” means that the nitrile group is attached to the basemolecule through an alkyl linker.

The compounds of Structural Formula I may contain one or more chiralcenters, and exist in different optically active forms. When compoundsof Structural Formula I contain one chiral center, the compounds existin two enantiomeric forms and the present invention includes bothenantiomers and mixtures of enantiomers, such as racemic mixtures. Theenantiomers may be resolved by methods known to those skilled in theart, for example by formation of diastereoisomeric salts which may beseparated, for example, by crystallization; formation ofdiastereoisomeric derivatives or complexes which may be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic esterification; or gas-liquid or liquidchromatography in a chiral environment, for example on a chiral supportfor example silica with a bound chiral ligand or in the presence of achiral solvent. It will be appreciated that where the desired enantiomeris converted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

When a compound represented by Structural Formula I has more than onechiral substituent it may exist in diastereoisomeric forms. Thediastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. The present invention includes each diastereoisomer ofcompounds of Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The present invention includes each conformational isomer ofcompounds of Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I may exist in zwitterionic formand the present invention includes each zwitterionic form of compoundsof Structural Formula I and mixtures thereof.

“Pharmaceutically-acceptable salt” refers to salts of the compounds ofthe Structural Formula I that are substantially non-toxic to mammals.Typical, pharmaceutically-acceptable salts include those salts preparedby reaction of the compounds of the present invention with a mineral ororganic acid or an organic or inorganic base. Such salts are known asbase addition salts, respectively. It should be recognized that theparticular counterion forming a part of any salt of this invention isnot of a critical nature, so long as the salt as a whole ispharmaceutically-acceptable and as long as the counterion does notcontribute undesired qualities to the salt as a whole.

By virtue of its acidic moiety, a compound of Structural Formula I formssalts with pharmaceutically acceptable bases. Some examples of baseaddition salts include metal salts such as aluminum; alkali metal saltssuch as lithium, sodium or potassium; and alkaline earth metal saltssuch as calcium and magnesium; and ammonium or substituted ammoniumsalts. Examples of substituted ammonium salts include, for instance,those with lower alkylamines such as trimethylamine, triethylamine;hydroxyalkylamines such as 2-hydroxyethylamine,bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine,cycloalkylamines such as bicyclohexylamine or dibenzylpiperidine,N-benzyl-β-phenethylamine, dehydroabietylamine,N,N′-bisdehydro-abietylamine, glucamine, N-methylglucamine; bases of thepyridine type such as pyridine, collidine, quinine or quinoline; andsalts of basic amino acids such as lysine and arginine.

These salts may be prepared by methods known to those skilled in theart.

In addition, it is generally not desirable to formulate pharmaceuticalscontaining substantial amounts of organic solvent (e.g., ethyl acetate)due to potential solvent toxicity to the recipient thereof and changesin potency of the pharmaceutical as a function of the solvent.

The term, “active ingredient” means the compounds generically describedby Structural Formula I as well as the salts of such compounds.

The term “pharmaceutically acceptable” means that the carrier, diluent,excipients and salt must be compatible with the other ingredients of thecomposition. Pharmaceutical compositions of the present invention areprepared by procedures known in the art using well-known and readilyavailable ingredients.

“Preventing” refers to reducing the likelihood that the recipient willincur or develop any of the pathological conditions described herein. Itis preferred that the recipient is thought to be susceptible to saidcondition. A preferred recipient may be a human.

“Treating” refers to mediating a disease or condition and preventing, ormitigating, its further progression or ameliorate the symptomsassociated with the disease or condition.

“Pharmaceutically-effective amount” means that amount of a compound, orof its salt thereof, that will elicit the biological or medical responseof a tissue, system, or, mammal. Such an amount can be administeredprophylactically to a patient thought to be susceptible to developmentof a disease or condition. Such amount when administeredprophylactically to a patient can also be effective to prevent or lessenthe severity of the mediated condition. Such an amount is intended toinclude an amount which is sufficient to modulate a PPAR alpha receptoror to prevent or mediate a disease or condition. Conditions prevented ortreated by PPARα receptors include diabetes mellitus, cardiovasculardisease, Syndrome X, obesity and gastrointestinal disease.

A “mammal” is an individual animal that is a member of the taxonomicclass Mammalia. The class Mammalia includes humans, monkeys,chimpanzees, gorillas, cattle, swine, horses, sheep, dogs, cats, mice,and rats.

Administration to a human is most preferred. The compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of cardiovascular disease, for raising serum HDLcholesterol levels, for lowering serum triglyceride levels and for lowerserum LDL cholesterol levels. Elevated triglyceride and LDL levels, andlow HDL levels, are risk factors for the development of heart disease,stroke, and circulatory system disorders and diseases.

The compounds and compositions of the present invention are also usefulfor treating and/or preventing obesity.

Further, these compounds and compositions are useful for the treatmentand/or prophylaxis of non-insulin dependent diabetes mellitus (NIDDM)with reduced or no body weight gains by the patients. Furthermore, thecompounds and compositions of the present invention are useful to treator prevent acute or transient disorders in insulin sensitivity, such assometimes occur following surgery, trauma, myocardial infarction, andthe like. The physician of ordinary skill will know how to identifyhumans who will benefit from administration of the compounds andcompositions of the present invention.

The present invention further provides a method for the treatment and/orprophylaxis of hyperglycemia in a human or non-human mammal whichcomprises administering an effective, non-toxic amount of a compound ofthe general formula (I), or a tautomeric form thereof and/or apharmaceutically acceptable salt thereof to a hyperglycemic human ornon-human mammal in need thereof.

They are useful as therapeutic substances in preventing or treatingSyndrome X, diabetes mellitus and related endocrine and cardiovasculardisorders and diseases in human or non-human animals.

The invention also relates to the use of a compound of Formula I asdescribed above, for the manufacture of a medicament for treating aPPARα mediated condition.

A therapeutically effective amount of a compound of Structural Formula Ican be used for the preparation of a medicament useful for treatingSyndrome X, diabetes, treating obesity, lowering tryglyceride levels,lowering serum LDL levels, raising the plasma level of high densitylipoprotein, and for treating, preventing or reducing the risk ofdeveloping atherosclerosis, and for preventing or reducing the risk ofhaving a first or subsequent atherosclerotic disease event in mammals,particularly in humans. In general, a therapeutically effective amountof a compound of the present invention typically reduces serumtriglyceride levels of a patient by about 20% or more, and increasesserum HDL levels in a patient. Preferably, HDL levels will be increasedby about 30% or more. In addition, a therapeutically effective amount ofa compound, used to prevent or treat NIDDM, typically reduces serumglucose levels, or more specifically HbA1c, of a patient by about 0.7%or more.

Advantageously, compositions containing the compound of StructuralFormula I or the salts thereof may be provided in dosage unit form,preferably each dosage unit containing from about 1 to about 500 mg beadministered although it will, of course, readily be understood that theamount of the compound or compounds of Structural Formula I actually tobe administered will be determined by a physician, in the light of allthe relevant circumstances.

When used herein Syndrome X includes pre-diabetic insulin resistancesyndrome and the resulting complications thereof, insulin resistance,non-insulin dependent diabetes, dyslipidemia, hyperglycemia obesity,coagulopathy, hypertension and other complications associated withdiabetes. The methods and treatments mentioned herein include the aboveand encompass the treatment and/or prophylaxis of any one of or anycombination of the following: pre-diabetic insulin resistance syndrome,the resulting complications thereof, insulin resistance, Type II ornon-insulin dependent diabetes, dyslipidemia, hyperglycemia, obesity andthe complications associated with diabetes including cardiovasculardisease, especially atherosclerosis.

The compositions are formulated and administered in the same generalmanner as detailed herein. The compounds of the instant invention may beused effectively alone or in combination with one or more additionalactive agents depending on the desired target therapy. Combinationtherapy includes administration of a single pharmaceutical dosagecomposition which contains a compound of Structural Formula I and one ormore additional active agents, as well as administration of a compoundof Structural Formula I and each active agent in its own separatepharmaceutical dosage formulation. For example, a compound of StructuralFormula I or thereof and an insulin secretogogue such as biguanides,thiazolidinediones, sulfonylureas, insulin, or α-glucosidose inhibitorscan be administered to the patient together in a single oral dosagecomposition such as a tablet or capsule, or each agent administered inseparate oral dosage formulations. Where separate dosage formulationsare used, a compound of Structural Formula I and one or more additionalactive agents can be administered at essentially the same time, i.e.,concurrently, or at separately staggered times, i.e., sequentially;combination therapy is understood to include all these regimens.

An example of combination treatment or prevention of atherosclerosis maybe wherein a compound of Structural Formula I or salts thereof isadministered in combination with one or more of the following activeagents: antihyperlipidemic agents; plasma HDL-raising agents;antihypercholesterolemic agents, fibrates, vitamins, aspirin, and thelike. As noted above, the compounds of Structural Formula I can beadministered in combination with more than one additional active agent.

Another example of combination therapy can be seen in treating diabetesand related disorders wherein the compounds of Structural Formula I,salts thereof can be effectively used in combination with, for example,sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors,other insulin secretogogues, insulin as well as the active agentsdiscussed above for treating atherosclerosis.

The compounds of the present invention, and the pharmaceuticallyacceptable salt thereof, have valuable pharmacological properties andcan be used in pharmaceutical compositions containing a therapeuticallyeffective amount of a compound of the present invention, orpharmaceutically acceptable salts thereof, in combination with one ormore pharmaceutically acceptable excipients. Excipients are inertsubstances such as, without limitation carriers, diluents, fillers,flavoring agents, sweeteners, lubricants, solubilizers, suspendingagents, wetting agents, binders, disintegrating agents, encapsulatingmaterial and other conventional adjuvants. Proper formulation isdependent upon the route of administration chosen. Pharmaceuticalcompositions typically contain from about 1 to about 99 weight percentof the active ingredient which is a compound of the present invention.

Preferably, the pharmaceutical formulation is in unit dosage form. A“unit dosage form” is a physically discrete unit containing a unit dose,suitable for administration in human subjects or other mammals. Forexample, a unit dosage form can be a capsule or tablet, or a number ofcapsules or tablets. A “unit dose” is a predetermined quantity of theactive compound of the present invention, calculated to produce thedesired therapeutic effect, in association with one or morepharmaceutically-acceptable excipients. The quantity of activeingredient in a unit dose may be varied or adjusted from about 0.1 toabout 1000 milligrams or more according to the particular treatmentinvolved.

The dosage regimen utilizing the compounds of the present invention isselected by one of ordinary skill in the medical or veterinary arts, inview of a variety of factors, including, without limitation, thespecies, age, weight, sex, and medical condition of the recipient, theseverity of the condition to be treated, the route of administration,the level of metabolic and excretory function of the recipient, thedosage form employed, the particular compound and salt thereof employed,and the like.

Preferably, the compounds of the present invention are administered in asingle daily dose, or the total daily dose may be administered individed doses, two, three, or more times per day. Where delivery is viatransdermal forms, of course, administration is continuous.

Suitable routes of administration of pharmaceutical compositions of thepresent invention include, for example, oral, eyedrop, rectal,transmucosal, topical, or intestinal administration; parenteral delivery(bolus or infusion), including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraven-tricular, intravenous, intraperitoneal, intranasal, orintraocular injections. The compounds of the invention can also beadministered in a targeted drug delivery system, such as, for example,in a liposome coated with endothelial cell-specific antibody.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, powders, sachets,granules, dragees, capsules, liquids, elixers, tinctures, gels,emulsions, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compound with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores.

For oral administration in the form of a tablet or capsule, the activeingredient may be combined with an oral, non-toxic,pharmaceutically-acceptable carrier, such as, without limitation,lactose, starch, sucrose, glucose, methyl cellulose, calcium carbonate,calcium phosphate, calcium sulfate, sodium carbonate, mannitol,sorbitol, and the like; together with, optionally, disintegratingagents, such as, without limitation, cross-linked polyvinyl pyrrolidone;maize, starch, methyl cellulose, agar, bentonite, xanthan gum, alginicacid, or a salt thereof such as sodium alginate, and the like; and,optionally, binding agents, for example, without limitation, gelatin,acacia, natural sugars, beta-lactose, corn sweeteners, natural andsynthetic gums, acacia, tragacanth, sodium alginate,carboxymethyl-cellulose, polyethylene glycol, waxes, and the like; and,optionally, lubricating agents, for example, without limitation,magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodiumbenzoate, sodium acetate, sodium chloride, talc, and the like. When adosage unit form is a capsule, it may contain, in addition to materialsof the above type, a liquid carrier such as a fatty oil.

Solid form formulations include powders, tablets and capsules. A solidcarrier can be one or more substance which may also act as flavoringagents, lubricants, solubilisers, suspending agents, binders, tabletdisintegrating agents and encapsulating material.

In powders, the carrier is a finely divided solid which is in admixturewith the finely divided active ingredient. In tablets, the activeingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Sterile liquid formulations include suspensions, emulsions, syrups, andelixirs. The active ingredient can be dissolved or suspended in apharmaceutically acceptable carrier, such as sterile water, sterileorganic solvent, or a mixture of both sterile water and sterile organicsolvent.

The active ingredient can also be dissolved in a suitable organicsolvent, for example, aqueous propylene glycol. Other compositions canbe made by dispersing the finely divided active ingredient in aqueousstarch or sodium carboxymethyl cellulose solution or in a suitable oil.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

All formulations for oral administration should be in dosages suitablefor such administration. Particularly suitable compositions for oraladministration are unit dosage forms such as tablets and capsules.

For parental administration the compounds of the present invention, orsalts thereof, can be combined with sterile aqueous or organic media toform injectable solutions or suspensions. Formulations for injection maybe presented in unit dosage form, such as in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The pharmaceutical forms suitablefor injectable use include sterile aqueous solutions or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersions. In all cases, the form must be sterile andmust be fluid to the extent that each syringability exists. It must bestable under the conditions of manufacture and storage and must bepreserved against any contamination. The carrier can be solvent ordispersion medium containing, for example, water, preferably inphysiologically compatible buffers such as Hanks's solution, Ringer'ssolution, or physiological saline buffer, ethanol, polyol (e.g.glycerol, propylene glycol and liquid polyethylene glycol), propyleneglycol and liquid polyethylene glycol), suitable mixtures thereof, andvegetable oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The injectable solutions prepared in this manner can then beadministered intravenously, intraperitoneally, subcutaneously, orintramuscularly, with intramuscular administration being preferred inhumans.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in a conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of a dry powderinhaler, or an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Pharmaceutical compositions of the present invention can be manufacturedin a manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes.

In making the compositions of the present invention, the activeingredient will usually be admixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, lyophilized solid or paste, semi-solid, orliquid material which acts as a vehicle, or can be in the form oftablets, pills, powders, lozenges, elixirs, suspensions, emulsions,solutions, syrups, aerosols (as a solid or in a liquid medium), orointment, containing, for example, up to 10% by weight of the activecompound. The compounds of the present invention are preferablyformulated prior to administration.

The following pharmaceutical formulations 1 and 2 are illustrative onlyand are not intended to limit the scope of the invention in any way.“Active Ingredient”, refers to a compound according to StructuralFormula I or salts thereof.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesiumstearate 10 Total 460 mg

Formulation 2

A tablet is prepared using the ingredients below:

Quantity (mg/tablet) Active Ingredient 250 Cellulose, microcrystalline400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mgThe components are blended and compressed to form tablets each weighing665 mg.

In yet another embodiment of the compounds of the present invention, thecompound is radiolabelled, such as with carbon-14, or tritiated. Saidradiolabelled or tritiated compounds are useful as reference standardsfor in vitro assays to identify new PPARα and or PPARδ agonists.

Synthesis

Compounds of the present invention have been formed as specificallydescribed in the examples. Further, many compounds were prepared as moregenerally as shown in the following schematic. Alternative synthesismethods may also be effective and are known to the skilled artisan.

Preparation 1 Preparation of(2S)-3-(4-Hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester

(2S)-3-(4-Hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester: Sodiumbis-(trimethyl-silyl)amide (440 ml, 0.44 mol, 1.0 M in THF) was cooledto −70° C. under a nitrogen atmosphere. A solution of4-benzyloxybenzaldehyde (85 g, 0.4 mol) and methyl methoxyacetate (52 g,0.5 mol) in THF (0.5 L) was added dropwise at −70° C. over 2 h, and themixture was stirred for an hour. A solution of concentrated HCl (85 mL)and water (85 mL) was added at −70° C. The resulting solution wasallowed to warm to ambient temperature and was extracted with MTBE(2×0.5 L). The combined extracts were washed with brine (0.5 L), dried(MgSO₄), filtered, and concentrated and dissolved in CH₂Cl₂ (700 mL) andpyridine (129 mL, 1.6 mol). The resulting solution was cooled in a waterbath and trifluoroacetic anhydride (85 mL, 0.6 mol) was added dropwiseunder nitrogen. The bath was removed, and the mixture was stirred atambient temperature for 16 h. The solution was cooled to 0° C. andconcentrated HCl (150 mL) in water (1 L) was added dropwise. The organiclayer was separated and concentrated, and ethyl acetate (0.5 L) wasadded. The resulting solution was treated with hydrogen gas under 50 psiin the presence of 5% Pd—C (80 g, 50% water wet) at ambient temperaturefor 16 h. The catalyst was filtered, and the filtrate was concentratedunder vacuum to give 122 g of Methyl3-(4-hydroxyphenyl)-2-methoxypropanoate as an oil. ¹H-NMR (CDCl₃) δ 7.1(d, 2H), 6.7 (d, 2H), 5.4 (s, 1H), 4.0 (m, 1H), 3.7 (s, 3H), 3.4 (s,3H), 3.0 (m, 1H); MS (ES) m/z 209.2 (M−1).

Methyl 3-(4-hydroxyphenyl)-2-methoxypropanoate (132 g, 0.631 mol) wasdissolved in methanol (700 mL) and 5N sodium hydroxide (631 mL, 3.16mol) was added dropwise at ambient temperature. The solution was stirredfor 16 h at ambient temperature. The methanol was removed under vacuum,and water (500 mL) was added. The mixture was extracted with MTBE (2×500mL). The aqueous solution was brought to pH=1 with concentrated HCl andthen extracted with MTBE (2×500 nL). The organic extracts were dried(MgSO₄), filtered, and concentrated under vacuum to give racemic3-(4-hydroxyphenyl)-2-methoxypropanoic acid as an oil (110 g), whichcrystallized upon standing. ¹H-NMR (DMSO): 7.0 (d, 2H); 6.6 (d, 2H); 4.0(m, 1H); 2.8 (m, 2H); MS (ES⁻) m/z 195.1 (M−1).

A slurry consisting of 3-(4-hydroxyphenyl)-2-methoxypropanoic acid(21.21 g, 0.1081 mol), (-)-cinchonidine (31.83 g, 0.1081 mol), and THF(424 mL) was heated briefly at reflux to give a red-brown solution. Themixture was cooled to ambient temperature and stirred for 3 days. Theresulting slurry was cooled to 0° C. for 4 h and filtered to give about17.06 g of the cinchonidine salt (71.2% ee by chiral HPLC). Thecinchonidine salt was slurried in THF, heated to reflux for 1 hour, andcooled to ambient temperature overnight. The mixture was cooled to 0° C.for 2 h and filtered to give about 14.87 g of the cinchonidine salt(83.0% ee by chiral HPLC). The cinchonidine salt was slurried again inTHF, and heated to reflux for 1 hour, and cooled to ambient temperature.The mixture was cooled to 0° C. for 2 h and filtered to give about 12.87g (24%) of the cinchonidine salt of(2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid (91.4% ee by chiralHPLC). Repeating the crystallization afforded compound of 98.1% ee. Thefree acid was obtained by suspending the salt (78 g) in 1N HCl solution(750 mL) and extracted with methyl tert-butyl ether (3×200 mL). Thecombined extracts were dried (Na₂SO₄) and concentrated to give about24.12 g (82%) of (2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid (96.7%ee by chiral HPLC). ¹H NMR (DMSO-d₆): δ 2.72-2.89 (m, 2H), 3.21 (s, 3H),3.8-3.87 (m, 1H), 6.64-6.67 (d, 2H), 6.97-7.02 (d, 2H),9.15 (s, broad,1H), 12.62 (s, broad, 1H); MS (ES⁺) m/z 219.0 ([M+Na]⁺), (ES⁻) m/z 195.1([M−H]⁻); [α]_(D)=−2.2° (c=1, MeOH).

A solution of (2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid (35 g) in140 ml of ethanol was mixed with 5.66 ml of concentrated sulfuric acidand stirred at room temperature until complete as indicated by HPLC. Theethanol was removed via vacuum distillation (55° C./28″Hg) and 110 ml ofwater was added. The pH was adjusted to about 7 to 8 with sodiumbicarbonate, and the mixture was extracted with add 50 ml ethyl acetate(3×50 mL). The organic layers were combined, washed with 50 ml 20% NaClsolution, dried with 15 g of magnesium sulfate, and concentrate productto afford ethyl 2S-2-methoxy-3-(4-hydorxyphenyl) propanoate as an oil.¹H-NMR (CDCl₃) δ 7.1 (d, 2H); 6.7 (d, 2H); 4.2 (m, 2H); 3.9 (m, 1H); 3.6(s, 3H); 2.95 (m, 2H); 1.25 (t, 3H); MS (ES): 223.2 (M−1).

Preparation 2 Step 1 3-(4-Benzyloxy-phenyl)-2-ethoxy-3-hydroxy-propionicacid ethyl ester

The title compound was prepared from 4-benzyloxybenzaldehyde, lithiumdiisopropylamide and ethyl 2-ethoxyacetate via the same procedure usedfor the preparation of 3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxypropionic acid methyl ester (example 9, step 1). MS (ES) for C₂₀H₂₄O₅[M+H₂O—H]⁺: 327, [M+Na]⁺: 367.4.

Step 2 3-(4-Benzyloxy-phenyl)-2-ethoxy-acrylic acid ethyl ester

The title compound was prepared from3-(4-Benzyloxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethyl ester(Preparation 2, step 1) via the same procedure used for the preparationof 3-(4-Benzyloxy-phenyl)-2-ethoxy-acrylic acid methyl ester. MS (ES)for C₂₀H₂₂O₄ [M+H]⁺: 327.2.

Step 3 3-(4-Benzyloxy-phenyl)-2-ethoxy-propionic acid methyl ester

The title compound was prepared from3-(4-Benzyloxy-phenyl)-2-ethoxy-acrylic acid ethyl ester (Preparation 2,step 2) (3.3 gr, 10.12 mmol) via the same procedure used for thepreparation of 3-(3-Benzyloxy-phenyl)-2-methoxy-propionic acid methylester (example 9, step 3) to produce an oil that was purified bychromatography (silica gel, hexanes/ethyl acetate 6:1) to produce twocompounds: 3-(4-Benzyloxy-phenyl)-propionic acid methyl ester (1.5 gr,Rf aprox. 0.65) and the desired compound (1.5 gr, Rf aprox. 0.2). MS(ES) for C₁₉H₂₂O₄ [M+NH₄]⁺: 332.3.

Step 4 2-Ethoxy-3-(4-hydroxy-phenyl)-propionic acid methyl ester

The title compound was prepared from3-(4-Benzyloxy-phenyl)-2-ethoxy-propionic acid methyl ester (Preparation2, step 3) via the same procedure used for the preparation of3-(3-Hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (example 9,step 4) to produce a yellow oil. MS (ES) for C₁₂H₁₆O₄ [M+H]⁺: 225.2,[M+NH₄]⁺: 242.2, [+Na]⁺: 247.2.

Preparation 3(2S)-2-methoxy-3-(4-{2-oxo-2-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethoxy}-phenyl)-propionicacid

Step 1: (2S)-3-(4-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionicacid ethyl ester

The compound of (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ester(Preparation 1), (1.2 g, 5.3 mmol) was dissolved in 25 ml of anhydrousTHF and NaH (380 mg, 15.8 mmol) was added portion wise. After about 5minutes, bromo-acetic acid tert-butyl ester was added dropwise at roomtemperature. The mixture was stirred for 2 hours at room temperature.The crude was dissolved in ethyl acetate (100 ml) and a solution of 5%HCl was added. The mixture was extracted with ethyl acetate (3×100 ml),and the combined organic layers were dried over (MgSO₄) and thenconcentrated under vacuum. The crude was purified by columnchromatography (silica gel, hexane/ethyl acetate 8.5:1.5) to afford ayellow oil.

Step 2: (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethylester

The compound of(2S)-3-(4-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acidethyl ester (PREPARATION 3, step 1) (1.2 gr, 3.5 mmol) was solved indichloromethane (5 ml) and trifluoroacetic acid was added (5 ml). Themixture was stirred for an hour, and the crude was concentrated toafford a yellow oil. ¹H-NMR (CDCl₃, 200.15 MHz): 7.16 (d, 2H, J=8.3),6.75 (d, 2H, J=8.3), 4.89 (s, 2H), 4.14 (c, 2H, J=6.9), 3.94 (t, 1H,J=6.9), 3.57 (dc, 1H), 3.35 (dc, 1H), 2.92 (d, 2H, J=6.9), 1.23-1.10(2t, 6H).

Step 3:(2S)-2-methoxy-3-(4-{2-oxo-2-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-(4-trifluoromethyl-phenyl)-piperazine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₃H₂₅F₃NO₅ [M+H]⁺: 467.

Preparation 43-(3-{[2-(4-ethyl-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid (isomer 1)

Step 1: 3-(3-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acidmethyl ester

The title compound was prepared from3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (example 9,step 4) via the same procedure used to prepare(2S)-3-(4-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acidethyl ester (PREPARATION 3, step 1) to produce a yellow oil. MS (ES) forC₁₇H₂₄O₆ [M+H]⁺: 325.

Step 2: 3-(3-carboxymethoxy-phenyl)-2-methoxy-propionic acid methylester

The title compound was prepared from3-(3-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acid methylester (PREPARATION 4, step 1) via the same procedure used to prepare(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) to produce a yellow oil. MS (ES) for C₁₃H₁₆O₆[M+H]⁺: 269.

Step 3:3-(3-{[2-(4-ethyl-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid (isomer-1)

The title compound was prepared from3-(3-carboxymethoxy-phenyl)-2-methoxy-propionic acid methyl ester(PREPARATION 4, step 2) and 2-(4-ethyl-phenyl)-ethylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₇NO₅ [M+H]⁺: 386.

Preparation 5(2S)-2-methoxy-3-[4-(1-methyl-1-octylcarbamoyl-ethoxy)-phenyl]-propionicacid

Step 1:(2S)-3-[4-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2-methoxy-propionicacid ethyl ester

The title compound was prepared from(2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ester (Preparation 1)and 2-bromo-2-methyl-propionic acid tert-butyl ester via the sameprocedure used to prepare(2S)-3-(4-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acidethyl ester (example 121, step 1) to produce a yellow oil.

¹H-NMR (CDCl₃, 200.15 MHz): δ 7.10 (d, 2H, J=8.3), 6.77 (d, 2H, J=8.3),4.17 (c, 2H, J=6.9), 3.90 (t, 1H, J=6.5), 3.34 (s, 3H), 2.93 (d, 2H,J=6.5), 1.55 (s, 3H), 1.43 (s, 9H), 1.23-1.4 (t, 3H, J=6.9).

Step 2:(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester

The title compound was prepared from(2S)-3-[4-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2-methoxy-propionicacid ethyl ester (PREPARATION 5, step 1) via the same procedure used toprepare (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethylester (example 121, step 2) to produce a yellow oil. ¹H-NMR (CDCl₃,200.15 MHz): 7.10 (d, 2H, J=8.3), 6.77 (d, 2H, J=8.3), 4.14 (c, 2H,J=6.9), 3.89 (t, 1H, J=6.5), 3.34 (s, 3H), 2.94 (d, 2H, J=6.5), 1.55 (s,6H), 1.19 (t, 3H, J=6.9).

Step 3:(2S)-2-methoxy-3-[4-(1-methyl-1-octylcarbamoyl-ethoxy)-phenyl]-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester (PREPARATION 5, step 2) and heptylamine via the sameprocedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₁H₃₃NO₅ [M+H]⁺: 380.

EXAMPLE 1(2S,1′R)-2-Ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

Step 1:(2S,1′R)-3-[4-(1′-benzyloxycarbonyl-ethoxy)-phenyl]-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from(2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid methyl ester (isomer 2of Preparation 2, step 4 after chiral separation) (2.9 mmol) and(2S)-2-hydroxy-propionic acid benzyl ester (4.35 mmol) via the sameprocedure used for the preparation of(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Preparation 1, step 2) and purified by chromatography (silica gel,hexanes/ethyl acetate 6:1, Rf 0.27) to produce a colorless oil. MS (ES)for C₂₃H₂₈O₆ [M+NH4]⁺: 418.2, [M+Na]⁺: 423.2.

Step 2: (2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionicacid

The title compound was prepared from(2S,1R)-3-[4-(1-benzyloxycarbonyl-ethoxy)-phenyl]-2-ethoxy-propionicacid ethyl ester (Preparation 1) via the same procedure used for thepreparation of 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methylester (example 9, step 4) to produce a yellow oil. MS (ES) for C₁₆H₂₂O₆[M+NH₄]⁺: 328.2.

Step 3:(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) (0.1 mmol) was dissolved in dichlromethane in a16×100 mm tube, triethylamine (0.15 mmol), eimethylaminopyridine (0.01mmol), PyBroP (0.2 mmol) and 2-(4-phenoxy-phenyl)-ethylamine (0.15 mmol)were added and the mixture was stirred overnight at room temperature.The mixture was concentrated to dryness under vacuum. The crude wasdissolved in MeOH and charged into a 500 mg SCX column (previouslypre-conditioned with MeOH). The column was washed (2×2 ml) with MeOH.The crude was concentrated, and the residue reconstituted in a mixtureof Ethanol (2 ml) and NaOH (1M in water, 1 mL), which was stirred atroom temperature until the hydrolysis was completed by HPLC-MS. Then HCl(1M in water) was added (until pH=3) and the solvent was eliminatedunder vacuum. The residue was reconstituted in CH₂Cl₂/H₂O and filteredthrough a hydrophobic syringe. The organic layer was separated,concentrated and purified by HPLC-MS to produce the compound as acolorless oil. MS (ES) for C₂₈H₃₁NO₆ [M+H]⁺: 478.2.

EXAMPLE 2(2S,1′R)-2-Ethoxy-3-(4-{1′-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from 2-(4-ethyl-phenyl)-ethylamine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₃₁NO₅ [M+H]⁺: 414.2.

EXAMPLE 3(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-trifluoromethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from2-(4-tifluoromethyl-phenyl)-ethylamine and(2S,1′R)-3-[4-(1′-Carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₃H₂₆F₃NO₅ [M+H]⁺: 454.2, [M−H]⁻: 452.2

EXAMPLE 4(2S,1′R)-3-{4-[1′-(4-tert-butyl-cyclohexylcarbamoyl)-ethoxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from a mixture of cis/trans (2:3) of4-tert-butyl-cyclohexylamine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil.

MS (ES) for C₂₄H₃₇NO₅ [M+H]⁺:420.3, [M+NH₄]⁺:442.3, [M+H]⁺: 4.18.2

EXAMPLE 5(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(2-ethoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from 2-(2-ethoxy-phenyl)-ethylamine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₃₁NO₆ [M+H]⁺: 430.2.

EXAMPLE 6(2S,1′R)-2-ethoxy-3-{4-[1′-(3-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from 3-trifluoromethyl-benzylamine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₄F₃NO₅ [M+H]⁺: 440.2.

EXAMPLE 7(2S,1′R)-2-ethoxy-3-{4-[1′-(3-fluoro-5-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from3-fluoro-5-trifluoromethyl-benzylamine and(2S,1′R)-3-[4-(1′-Carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₃F₄NO₅ [M−H]⁻: 456.1.

EXAMPLE 8(2S,1′R)-3-(4-{1′-[(biphenyl-3-ylmethyl)-carbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared from C-biphenyl-3-yl-methylamine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-Ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₇H₂₉NO₅ [M+H]⁺: 448.2.

EXAMPLE 9(2S,1′R)-3-(4-{1′-[2-(3-chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared from 2-(3-chloro-phenyl)-ethylamine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₆ClNO₅ [M+H]⁺: 420.2.

EXAMPLE 10(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(3-fluoro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from[2-(3-fluoro-phenyl)-ethyl]-methyl-amine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₆FNO₅ [M+H]⁺: 404.2.

EXAMPLE 11(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(2-fluoro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from[2-(2-fluoro-phenyl)-ethyl]-methyl-amine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₆FNO₅ [M+H]⁺: 404.2.

EXAMPLE 12(2S,1′R)-3-(4-{1′-[2-(2,4-dichloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared from 2-(2,4-dichloro-phenyl)-ethylamineand (2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₅Cl₂NO₅ [M+H]⁺: 454.1.

EXAMPLE 13(2S,1′R)-3-(4-{1′-[2-(2,6-dichloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared from 2-(2,6-dichloro-phenyl)-ethylamineand (2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₅Cl₂NO₅ [M+H]⁺: 454.1.

EXAMPLE 14(2S,1′R)-2-ethoxy-3-[4-(1′-heptylcarbamoyl-ethoxy)-phenyl]-propionicacid

The title compound was prepared from heptylamine and(2S,1′R)-3-[4-(1′-Carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethycarbmoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₁H₃₃NO₅ [M+H]⁺: 380.3.

EXAMPLE 15(2S,1′R)-3-(4-{1′-[2-(2-chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared from 2-(2-chloro-phenyl)-ethylamine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₆ClNO₅ [M+H]⁺: 420.2.

EXAMPLE 16(2S,1′R)-3-(4-{1′-[2-(4-tert-butyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared from 2-(4-tert-butyl-phenyl)-ethylamineand (2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₆H₃₅NO [M+H]⁺: 442.5.

EXAMPLE 17(2S,1′R)-2-ethoxy-3-{4-[1′-(4-fluoro-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from 4-fluoro-benzylamine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarmoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₁H₂₄FNO₅ [M+H]⁺: 390.4.

EXAMPLE 18(2S,1′R)-2-ethoxy-3-{4-[1′-(4-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from 4-trifluoromethyl-benzylamine and(2S,1′R)-3-[4-(1′-Carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₄F₃NO₅ [M+H]⁺: 440.3.

EXAMPLE 19(2S,1′R)-2-ethoxy-3-{4-[1′-(2-thiophen-2-yl-ethylcarbamoyl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from 2-thiophen-2-yl-ethylamine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethycarmoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a yellow oil. MS (ES) for C₂₀H₂₅NO₅S[M+H]⁺: 392.3.

EXAMPLE 20(2S,1′R)-2-ethoxy-3-(4-{1′-[(thiophen-2-ylmethyl)-carbamoyl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from C-thiophen-2-yl-methylamine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a yellow oil. MS (ES) for C₁₉H₂₃NO₅S[M+H]⁺: 378.3.

EXAMPLE 21(2S,1′R)-3-{4-[1′-(4-tert-butyl-benzylcarbamoyl)-ethoxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from 4-tert-butyl-benzylamine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethycarmoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₅H₃₃NO₅ [M+H]⁺: 428.4.

EXAMPLE 22(2S,1′R)-3-{4-[1′-(4-tert-butyl-phenylcarbamoyl)-ethoxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from 4-tert-butyl-phenylamine and(2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarmoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₃₁NO₅ [M+H]⁺: 414.4.

EXAMPLE 23(2S,1′R)-3-{4-[1′-(4-trans-tert-butyl-cyclohexylcarbamoyl-ethoxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from trans 4-tert-butyl-cyclohexylamineand (2S,1′R)-3-[4-(1′-carboxy-ethoxy)-phenyl]-2-ethoxy-propionic acid(Example 1, step 2) via the same procedure used for the preparation of(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₃₇NO₅ [M+H]⁺:420.3, [M+NH₄]⁺: 442.3.

EXAMPLE 24(2S)-3-[4-({ethyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-carbamoyl}-methoxy)-phenyl]-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) andethyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₃₁NO₆ [M+H]⁺: 430.

EXAMPLE 25(2S)-2-methoxy-3-{4-[(1-naphthalen-1-yl-ethylcarbamoyl)-methoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-naphthalen-1-yl-ethylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₂₅NO₅ [M+H]⁺: 408.

EXAMPLE 26(2S)-2-methoxy-3-{4-[(1-Phenyl-ethylcarbamoyl)-methoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-phenyl-ethylamine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₀H₂₃NO₅ [M+H]⁺: 358.

EXAMPLE 27(2S)-2-methoxy-3-(4-{[methyl-(1-phenyl-ethyl)-carbamoyl]-methoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and methyl-(1-phenyl-ethyl)-amine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₁H₂₅NO₅ [M+H]⁺: 372.

EXAMPLE 28(2S)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and (4-fluoro-phenyl)-piperidin-4-yl-methanonevia the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₂₆FNO₆ [M+H]⁺: 444.

EXAMPLE 29(2S)-3-(4-{2-[4-(4-chloro-benzoyl)-piperidin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and (4-chloro-phenyl)-piperidin-4-yl-methanonevia the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a yellow oil. MS (ES) forC₂₄H₂₆ClNO₆ [M+H]⁺: 460.

EXAMPLE 30(2S)-2-methoxy-3-{4-[(1-methoxycarbonyl-2-phenyl-ethylcarbamoyl)-methoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 2-amino-3-phenyl-propionic acid methyl estervia the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₅NO₇ [M+H]⁺: 416.

EXAMPLE 31(2S)-3-[4-(2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-2-oxo-ethoxy)-phenyl]-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and1-[(4-chloro-phenyl)-phenyl-methyl]-piperazine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₉H₃₁ClN₂O₅ [M+H]⁺: 524.

EXAMPLE 32(2S)-3-[4-({[(4-chloro-phenyl)-phenyl-methyl]-carbamoyl}-methoxy)-phenyl]-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and C-(4-chloro-phenyl)-C-phenyl-methylamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a yellow oil. MS (ES) forC₂₅H₂₄ClNO₅ [M+H]⁺: 454.

EXAMPLE 32A(2S)-3-(4-{[butyl-(1-phenyl-ethyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and butyl-(1-phenyl-ethyl)-amine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₃₁NO₅ [M+H]⁺414.

EXAMPLE 33(2S)-3-{4-[(3,3-diphenyl-propylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 3,3-eiphenyl-propylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a yellow oil. MS (ES) for C₂₇H₂₉NO₅[M+H]⁺: 448.

EXAMPLE 34(2S)-3-(4-{[benzyl-(2-ethoxycarbonyl-ethyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 3-benzylamino-propionic acid ethyl ester viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₂₉NO₇ [M+H]⁺: 444.

EXAMPLE 35(2S)-2-methoxy-3-(4-{[3-(methyl-phenyl-amino)-propylcarbamoyl]-methoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and N1-methyl-N1-phenyl-propane-1,3-diamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₈N₂O₅ [M+H]⁺: 401.

EXAMPLE 36(2S)-2-methoxy-3-(4-{[2-(4-methoxy-phenoxy)-ethylcarbamoyl]-methoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 2-(4-methoxy-phenoxy)-ethylamine via thesame procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₁H₂₅NO₇ [M+H]⁺: 404.

EXAMPLE 37(2S)-2-methoxy-3-{4-[(4-phenoxy-phenylcarbamoyl)-methoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 4-phenoxy-phenylamine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₂₃NO₆ [M+H]⁺: 421.

EXAMPLE 382-methoxy-3-{3-[(4-phenoxy-phenylcarbamoyl)-methoxy]-phenyl}-propionicacid (isomer 1)

The title compound was prepared from3-(3-carboxymethoxy-phenyl)-2-methoxy-propionic acid methyl ester(PREPARATION 4, step 2) and 4-phenoxy-phenylamine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₂₃NO₆ [M+H]⁺: 322.

EXAMPLE 39(2S)-3-{4-[1-(4-tert-butyl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester (PREPARATION 5, step 2) and4-cis/trans-tert-butyl-cyclohexylamine via the same procedure used forthe preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₃₇NO₅ [M+H]⁺: 420.

EXAMPLE 40(2S)-2-methoxy-3-(4-{1-methyl-1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester (PREPARATION 5, step 2) and 4-phenoxy-phenylamine via thesame procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₈H₃₁NO₆ [M+H]⁺: 478.

EXAMPLE 41(2S)-3-(4-{1-[2-(2-ethoxy-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester (PREPARATION 5, step 2) and 2-(2-ethoxy-phenyl)-ethylaminevia the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₃₁NO₆ [M+H]⁺: 430.

EXAMPLE 422-methoxy-2-methyl-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionicacid

The title compound was prepared from3-(4-carboxymethoxy-phenyl)-2-methoxy-2-methyl-propionic acid methylester 2-(4-phenoxy-phenyl)-ethylamine via the same procedure used forthe preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarmoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₇H₂₉NO₆ [M+H]⁺: 464.

EXAMPLE 432-methoxy-3-(4-{1-methyl-1-[2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester (PREPARATION 5, step 2) and2-(3-trifluoromethyl-phenyl)-ethylamine via the same procedure used forthe preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₃H₂₆F₃NO₅ [M−H]⁻: 452.

EXAMPLE 44(2S)-2-methoxy-3-{4-[1-methyl-1-(3-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester (PREPARATION 5, step 2) and 3-trifluoromethyl-benzylaminevia the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₄F₃NO₅ [M−H]⁻: 438.

EXAMPLE 45(2S)-3-(4-{1-[2-(2-chloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester (PREPARATION 5, step 2) and 2-(2-chloro-phenyl)-ethylaminevia the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₆ClNO₅ [M−H]⁻: 420.

EXAMPLE 46(2S)-3-(4-{1-[(biphenyl-3-ylmethyl)-carbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester (PREPARATION 5, step 2) and C-biphenyl-3-yl-methylamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₇H₂₉NO₅ [M−H]⁻: 446.

EXAMPLE 47(2S)-3-(4-{1-[2-(2,5-dimethoxy-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester (PREPARATION 5, step 2) and2-(2,5-dimethoxy-phenyl)-ethylamine via the same procedure used for thepreparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₃₁NO₇ [M−H]⁻: 445.

EXAMPLE 48(2S)-3-(4-{1-[2-(2-fluoro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester (PREPARATION 5, step 2) and 2-(2-fluoro-phenyl)-ethylaminevia the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₆FNO₅ [M−H]⁻: 402.

EXAMPLE 49(2S)-2-ethoxy-3-(4-{1-methyl-1-[2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

Step 1:(2S)-3-[4-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionicacid ethyl ester

The title compound was prepared(2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (example251, step 3) and 2-bromo-2-methyl-propionic acid tert-butyl ester viathe same procedure used to prepare(2S)-3-(4-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acidethyl ester (PREPARATION 3, step 1) to produce a yellow oil.

MS (ES) for C₂₁H₃₂O₆ [M+H]⁺: 381.

Step 2: (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from(2S)-3-[4-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionicacid ethyl ester (EXAMPLE 49, step 1) via the same procedure used toprepare (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethylester (PREPARATION 3, step 2) to produce a yellow oil.

MS (ES) for C₁₇H₂₄O₆ [M+H]⁺: 325.

Step 3:(2S)-2-ethoxy-3-(4-{1-methyl-1-[2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acidethyl ester (EXAMPLE 49, step 2) and2-(4-trifluoromethyl-phenyl)-ethylamine via the same procedure used forthe preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₂₈F₃NO₅ [M−H]⁻: 466.

EXAMPLE 50(2S)-2-ethoxy-3-{4-[1-(3-fluoro-5-trifluoromethyl-benzylcarbamoyl)-1-methyl-ethoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acidethyl ester (EXAMPLE 49, step 2) and3-fluoro-5-trifluoromethyl-benzylamine via the same procedure used forthe preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₃H₂₅F₄NO₅ [M−H]⁻: 470.

EXAMPLE 51(2S)-3-(4-{1-[2-(2-chloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(1-varboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acidethyl ester (EXAMPLE 49, step 2) and 2-(2-chloro-phenyl)-ethylamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₃H₂₈Cl₄NO₅ [M−H]⁻: 434.

EXAMPLE 52(2S)-3-(4-{1-[(biphenyl-3-ylmethyl)-carbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acidethyl ester (EXAMPLE 49, step 2) and C-biphenyl-3-yl-methylamine via thesame procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₈H₃₁NO₅ [M−H]⁻: 462.

EXAMPLE 53(2S)-3-(4-{1-[2-(3-chloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acidethyl ester (EXAMPLE 49, step 2) and 2-(3-chloro-phenyl)-ethylamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₃H₂₈ClNO₅ [M−H]⁻: 434.

EXAMPLE 54(2S)-3-(4-{1-[2-(2,5-dimethoxy-phenyl)-ethylcarbamoyl]-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acidethyl ester (EXAMPLE 49, step 2) and 2-(2,5-dimethoxy-phenyl)-ethylaminevia the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₅H₃₃NO₇ [M−H]⁻: 458.

EXAMPLE 55(2S)-2-ethoxy-3-(4-{1-[2-(2-fluoro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acidethyl ester (EXAMPLE 49, step 2) and 2-(2-fluoro-phenyl)-ethylamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₃H₂₈FNO₅ [M−H]⁻: 416.

EXAMPLE 56(2S)-3-{3-[1-(4-tert-butyl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-2-methoxy-propionicacid

Step 1:(2S)-3-[3-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2-methoxy-propionicacid methyl ester

The title compound was prepared from3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (example 9,step 4) and 2-bromo-2-methyl-propionic acid tert-butyl ester via thesame procedure used for the preparation of(2S)-3-(4-tert-butoxycarbonyl-methoxy-phenyl)-2-methoxy-propionic acidethyl ester (PREPARATION 3, step 1) to produce a yellow oil. ¹H-NMR(CDCl₃, 200.15 MHz): δ 7.13-7.09 (m, 1H), 6.84-6.69 (m, 3H), 3.95-3.89(dd, 1H, J=6.5, 4.4), 3.7 (s, 3H), 3.34 (s, 3H), 2.94-2.90 (m, 2H), 1.50(s, 6H), 1.43 (s, 9H).

Step 2:(2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidmethyl ester

The title compound was prepared from3-[3-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2-methoxy-propionicacid methyl ester (EXAMPLE 56, step 1) via the same procedure used toproduce (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethylester (PREPARATION 3, step 2) to produce a yellow oil. ¹H-NMR (CDCl3,200.15 MHz): δ 7.19-7.15 (m, 1H), 6.96-6.79 (m, 3H), 3.96-3.89 (dd, 1H,J=6.5, 4.4), 3.70 (s, 3H), 3.33 (s, 3H), 2.98-2.94 (m, 2H), 1.55 (s,6H).

Step 3:(2S)-3-{3-[1-(4-tert-butyl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidmethyl ester (EXAMPLE 56, step 2) and4-tert-cis/trans-Butyl-cyclohexylamine via the same procedure used forthe preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₃₇NO₅ [M−H]⁻: 418.

EXAMPLE 57(2S)-3-(3-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidmethyl ester (EXAMPLE 56, step 2) and 2-(4-ethyl-phenyl)-ethylamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₃₁NO₅ [M−H]⁻: 412.

EXAMPLE 58(2S)-2-methoxy-3-(3-{1-methyl-1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidmethyl ester (EXAMPLE 56, step 2) and 4-phenoxy-phenyl amine via thesame procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₈H₃₁NO₆ [M−H]⁻: 476.

EXAMPLE 59(2S)-3-{3-[1-(3-fluoro-5-trifluoromethyl-benzylcarbamoyl)-1-methyl-ethoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidmethyl ester (EXAMPLE 56, step 2) and3-fluoro-5-trifluoromethyl-benzylamine amine via the same procedure usedfor the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₃F₄NO₅ [M−H]⁻: 456.

EXAMPLE 60(2S)-3-(3-{1-[(biphenyl-3-ylmethyl)-carbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidmethyl ester (EXAMPLE 56, step 2) and C-biphenyl-3-yl-methylamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₇H₂₈NO₅ [M−H]⁻: 446.

EXAMPLE 61(2S)-3-(3-{1-[2-(3-chloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidmethyl ester (EXAMPLE 56, step 2) and 2-(3-chloro-phenyl)-ethylamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₉ClNO₅ [M−H]⁻: 418.

EXAMPLE 62(2S)-2-methoxy-3-{4-[(1-phenyl-ethylcarbamoyl)-methoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-phenyl-ethylamine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a yellow oil. MS (ES) For C₂₀H₂₃NO₅[M+H]⁺: 358.

EXAMPLE 63(2S)-3-(3-{1-[2-(2,4-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidmethyl ester (EXAMPLE 56, step 2) and 2-(2,4-dichloro-phenyl)-ethylaminevia the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil.

MS (ES) for C₂₂H₂₅ClNO₅ [M]+: 454, [M+2]+: 456.

EXAMPLE 64(2S)-3-(3-{1-[2-(2,6-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidmethyl ester (EXAMPLE 56, step 2) and 2-(2,6-dichloro-phenyl)-ethylaminevia the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₅ClNO₅ [M]+: 454, [M+2]+: 456.

EXAMPLE 65(2S)-3-[3-(1-heptylcarbamoyl-1-methyl-ethoxy)-phenyl]-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidmethyl ester (EXAMPLE 56, step 2) and heptylamine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₁H₃₃NO₅ [M+H]⁺: 480.

EXAMPLE 66(2S)-3-(4-{1-[2-(2,4-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester (PREPARATION 5, step 2) and2-(2,4-dichloro-phenyl)-ethylamine via the same procedure used for thepreparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₅Cl₂NO₅ [M−H]⁻: 452, [M+H]: 454.

EXAMPLE 67(2S)-3-(4-{1-[2-(2,4-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester (PREPARATION 5, step 2) and2-(2,4-dichloro-phenyl)-ethylamine via the same procedure used for thepreparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₅Cl₂NO₅ [M−H]⁻: 452, [M+H]⁻: 454.

EXAMPLE 68(2S)-3-(4-{1-[2-(2,6-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acidethyl ester (EXAMPLE 49, step 2) and 2-(2,6-dichloro-phenyl)-ethylaminevia the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₃H₂₇Cl₂NO₅ [M−H]⁻: 466, [M+H]⁻: 468.

EXAMPLE 69(2S)-2-ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acidethyl ester (EXAMPLE 49, step 2) and 2-(4-ethyl-phenyl) ethylamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₅H₃₃NO₅ [M+H]⁺: 428.

EXAMPLE 70(2S)-2-ethoxy-3-(4-{1-[2-(2-ethoxy-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acidethyl ester (EXAMPLE 49, step 2) and 2-(2-ethoxy-phenyl)-ethylamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₅H₃₃NO₆ [M+H]⁺: 444.

EXAMPLE 71(2S)-2-ethoxy-3-[4-(1-heptylcarbamoyl-1-methyl-ethoxy)-phenyl]-propionicacid

The title compound was prepared from(2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acidethyl ester (EXAMPLE 49, step 2) and hepthylamine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₃₃NO₅ [M+H]⁺: 394.

Preparation 6(R,S)-3-[4-(1-Benzyoxycarbonyl-ethoxy)-phenyl]-2-ethoxy-priopionic acidethyl ester

To a solution of 2-(S)-hydroxypropionic acid benzyl ester (0.966 g, 5.36mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester(1.16 g, 4.88 mmol) in THF (30 ml) was added the triphenyl phosphine(1.66 g, 6.34 mmol). The mixture was cooled to 0° C. and added the DIAD(diisopropyl azodicarboxylate) (1.18 g, 5.86 mmol) dropwise over 5minutes. The reaction mixture was stirred for 18 hours while warmed toroom temperature. The reaction was quenched with water (2 ml) andconcentrated to a residue, purified by silica gel chromatography with20% EtOAc/Hexanes to afford product (1.05 g, 49%) and recovered startingmaterial ((S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester,0.31 g).

Preparation 7 (R,S)-3-[4-(1-Carboxy-ethoxy)-phenyl]-2-ethoxy-propionicacid ethyl ester

To a solution of(R,S)-3-[4-(1-benzyloxycarbonyl-ethoxy)-phenyl]-2-ethoxy-propionic acidethyl ester (1.05 g, 2.63 mmol) in EtOH (20 ml) and H₂O (0.5 ml) wasadded a slurry of Pd—C (5%, 100 mg) in EtOH (10 ml). The suspension washydrogenated under balloon pressure for 2 hours. The mixture wasfiltered through a pad of celite and concentrated to a residue, theresidue was then purified by silica gel chromatography withEtOAc/Hexanes (25% to 100%) to afford the acid product (550 mg, 68%).

Preparation 8(R,S)-3-(4-{1-[2-(3-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid

A solution of (R,S)-3-[4-(1-carboxy-ethoxy)-phenyl]-2-ethoxy-propionicacid ethyl ester (310 mg, 1.00 mmol) in CH₂Cl₂ (35 ml) was treated withDMAP (207 mg, 1.70 mmol) and EDC (286 mg, 1.50 mmol). The mixture wasstirred at room temperature for 10 minutes and then treated with3-chlorophenyl ethylamine (201 mg, 1.3 mmol). The reaction mixture wasstirred for 2 hours and quenched with NH₄Cl (aq), extracted with CH₂Cl₂(2×35 ml) and dried over Na₂SO₄, purified on silica gel column withEtOAc/Hexanes (20-35%) to yield the intermediate ester product (291 mg,65%).

The ethyl ester was then dissolved in methanol (2.0 ml) and THF (1.0ml), and the solution was treated with NaOH (2.0 N, 3.0 ml). Thereaction mixture was stirred at room temperature for 18 hours andneutralized with HCl (1.0 N, 6.0 ml) to pH=7 and concentrated. Extractedwith EtOAc (3×20 ml), dried over Na₂SO₄, purified on silica gel columnwith EtOAc/Hexanes (35%-100%) and MeOH/EtOAc (5%) to yield the finalacid product (130 mg, 29% for two steps).

Preparation 9(S,S)-3-[4-(1-tert-Butoxycarbonyl-ethoxy)-phenyl]-2-ethoxy-propionicacid ethyl ester

To a solution of 2-(R)-hydroxypropionic acid tert-butyl ester (1.23 g,8.44 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethylester (2.01 g, 8.44 mmol) in THF (100 ml) was added the triphenylphosphine (2.21 g, 8.44 mmol). The mixture was cooled to 0° C. and addedthe DIAD (diisopropyl azodicarboxylate) (1.70 g, 8.44 mmol) dropwiseover 5 minutes. The reaction mixture was stirred for 18 hours whilewarmed to room temperature. The reaction was quenched with water (2 ml)and concentrated to a residue, purified by silica gel chromatographywith 20% EtOAc/Hexanes to afford product (0.99 g, 32%) and recoveredstarting material ((S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acidethyl ester, 0.85 g).

Preparation 10 (S,S)-3-[4-(1-Carboxy-ethoxy)-phenyl]-2-ethoxy-propionicacid ethyl ester

A solution of(S,S)-3-[4-(1-tert-butoxycarbonyl-ethoxy)-phenyl]-2-ethoxy-propionicacid ethyl ester (1.10 g, 3.00 mmol) in CH₂Cl₂ (5.0 ml) and TFA (4.0 ml)and water (0.2 ml) was stirred for 12 hours. The mixture wasconcentrated to a residue and purified by silica gel chromatography withEtOAc/Hexanes (50%) to afford the acid product (0.91 g, 98%).

EXAMPLE 74A(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid

A solution of (S,S)-3-[4-(1-carboxy-ethoxy)-phenyl]-2-ethoxy-propionicacid ethyl ester (46.5 mg, 0.150 mmol) in CH₂Cl₂ (2 ml) was treated withDMAP (27 mg, 0.225 mmol) and EDC (43 mg, 0.225 mmol). The mixture wasstirred at room temperature for 10 minutes and then treated with2-chlorophenyl ethylamine (47 mg, 0.300 mmol). The reaction mixture wasstirred for 2 hours and quenched with NH₄Cl (aq), extracted with CH₂Cl₂(2×5 ml) and dried over Na₂SO₄, purified on silica gel column withEtOAc/Hexanes (25%) to yield the intermediate ester product.

The ethyl ester was then dissolved in methanol (0.5 ml) and THF (0.25ml), and the solution was treated with NaOH (2.0 N, 0.5 ml). Thereaction mixture was stirred at room temperature for 18 hours andneutralized with HCl (1.0 N, 1.0 ml) to pH=7 and concentrated. Extractedwith EtOAc (3×2 ml), dried over Na₂SO₄, purified on silica gel columnwith EtOAc/Hexanes (35%-100%) and MeOH/EtOAc (5%) to yield the finalacid product (23 mg, 37% for two steps).

2-Ethoxy-3-{4-[1-(3-trifluoromethyl-phenylethylcarbamoyl)-ethoxy]-phenyl}-propionicacid,

¹H NMR (400 MHz, CDCl₃): δ 1.07 (br s, 3H), 1.46 (d, 3H, J=6.8 Hz),2.80-3.01 (m, 4H), 3.28-3.32 (m, 1H), 3.48-3.58 (m, 3H), 3.88 (br s,1H), 4.58 (q, 1H, J=6.4 Hz), 6.57-6.71 (m, 1H), 6.73 (d, 2H, J=7.8 Hz),6.98-7.18 (m, 5H), 7.28 (d, 1H, J=7.8 Hz).

MS (MH+): 420.2

EXAMPLE 75 2-Ethoxy-3-[4-(1-hexylcarbamoyl-ethoxy)-phenyl]-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹HNMR (400 MHz, CDCl₃): δ 0.84 (t, 3H, J=6.8 Hz), 1.17 (t, 3H,J=6.7 Hz), 1.22-1.27 (m, 8H), 1.44 (t, 2H, J=6.8 Hz), 1.54 (d, 3H, J=6.8Hz), 2.93-2.98 (dd, 1H, J=7.3 Hz, 13.7 Hz), 3.04-3.08 (dd, 1H, J=4.2 Hz,14.3 Hz), 3.41-3.46 (m, 1H), 3.58-3.64 (m, 1H), 4.03 (dd, 1H, J=4.4 Hz,7.8 Hz), 4.64 (q, 1H, J=6.8 Hz), 6.46 (t, 1H, J=5.4 Hz), 6.82 (d, 2H,J=8.3 Hz), 7.18 (d, 2H, J=8.8 Hz),

MS (MH+): 366.2

EXAMPLE 763-{4-[1-(4-tert-Butyl-cyclohexylcarbamoyl)-ethoxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹H NMR (400 MHz, CDCl₃, major isomer): δ 0.81 (s, 9H), 0.88-0.98(m, 3H), 1.05-1.17 (m, 6H), 1.51 (d, 3H, J=6.8 Hz), 1.70-1.88 (m, 3H),1.98-2.01 (m, 1H), 2.84-2.90 (dd, 1H, J=7.3 Hz, 13.7 Hz), 2.99-3.04 (dd,1H, J=4.2 Hz, 14.3 Hz), 3.31 (br s, 1H), 3.54-3.57 (m, 1H), 3.64-3.72(m, 1H), 3.95 (br s, 1H), 4.60 (q, 1H, J=6.8 Hz), 6.27 (d, 1H, J=8.3Hz), 6.82 (d, 2H, J=8.3 Hz), 7.18 (d, 2H, J=7.8 Hz),

MS (MH+): 420.3

EXAMPLE 772-Ethoxy-3-{4-[1-(3-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹H NMR (400 MHz, CDCl₃): δ 1.07 (t, 3H, J=6.7 Hz), 1.52 (d, 3H,J=6.8 Hz), 2.82-2.89 (dd, 1H, J=7.3 Hz, 13.7 Hz), 2.95-3.02 (dd, 1H,J=4.2 Hz, 14.3 Hz), 3.27-3.30 (m, 1H), 3.50-3.54 (m, 1H), 3.92 (dd, 1H,J=4.4 Hz, 7.8 Hz), 4.47 (d, 2H, J=5.9 Hz), 4.64 (q, 2H, J=7.3 Hz), 6.76(d, 2H, J=7.3 Hz), 6.06-7.14(m, 3H), 7.32-7.46 (m, 4H); MS (MH+): 440.2.

EXAMPLE 782-Ethoxy-3-{4-[1-(5-fluoro-3-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹H NMR (400 MHz, CDCl₃): δ 1.07 (t, 3H, J=6.7 Hz), 1.53 (d, 3H,J=6.8 Hz), 2.82-2.89 (dd, 1H, J=7.3 Hz, 13.7 Hz), 2.95-3.02 (dd, 1H,J=4.2 Hz, 14.3 Hz), 3.27-3.35 (m, 1H), 3.53-3.58 (m, 1H), 3.93 (dd, 1H,J=4.4 Hz, 7.8 Hz), 4.40-4.50 (m, 2H), 4.62 (q, 1H, J=6.8 Hz), 6.76 (d,2H, J=7.3 Hz), 7.00 (d, 1H, J=8.8 Hz), 7.13-7.20 (m, 5H); MS (MH+):486.1.

EXAMPLE 792-Ethoxy-3-{4-[1-(3-phenyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹H NMR (400 MHz, CDCl₃): δ 1.02 (t, 3H, J=6.7 Hz), 1.52 (d, 3H,J=6.8 Hz), 2.78-2.84 (dd, 1H, J=7.3 Hz, 13.7 Hz), 2.95-3.02 (dd, 1H,J=4.2 Hz, 14.3 Hz), 3.22-3.27 (m, 1H), 3.48-3.52 (m, 1H), 3.89 (dd, 1H,J=4.4 Hz, 7.8 Hz), 4.40-4.50 (m, 3H), 6.75 (d, 2H, J=7.3 Hz), 7.00 (brs, 1H), 7.10 (d, 2H, J=7.8 Hz), 7.28-7.49 (m, 9H); MS (MH+): 448.2.

EXAMPLE 802-Ethoxy-3-{4-[1-(4-phenoxy-phenylethylcarbamoyl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹H NMR (400 MHz, CDCl₃): δ 1.16 (t, 3H, J=6.7 Hz), 1.52 (d, 3H,J=6.8 Hz), 2.65-2.71 (dd, 1H, J=6.9 Hz, 13.7 Hz), 2.74-2.80 (dd, 1H,J=6.3 Hz, 12.7 Hz), 2.96-2.99 (m, 1H), 3.04-3.08 (m, 1H), 3.40-3.44 (m,2H), 3.56-3.64 (m, 2H), 4.03 (br s, 1H), 4.60 (q, 1H, J=6.4 Hz), 6.48(br s, 1H), 6.76 (d, 2H, J=7.8 Hz), 6.85-6.88 (m, 2H), 6.96-7.00 (m,4H), 7.07-7.17 (m, 3H), 7.30-7.35 (m, 2H); MS (MH+): 506.2.

EXAMPLE 812-Ethoxy-3-{4-[1-(3-trifluoromethyl-phenylethylcarbamoyl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹H NMR (400 MHz, CDCl₃): δ 1.00 (br s, 3H), 1.43 (d, 3H, J=6.8Hz), 2.73-2.88 (m, 3H), 2.96-3.00 (m, 1H), 3.21-3.26 (m, 1H), 3.46-3.52(m, 3H), 3.88 (br s, 1H), 4.60 (q, 1H, J=6.4 Hz), 6.63-6.69 (m, 3H),7.10 (d, 1H, J=7.8 Hz), 7.20 (d, 1H, J=7.8 Hz), 7.29-7.36 (m, 2H), 7.42(d, 1H, J=7.8 Hz); MS (MH+): 454.2.

EXAMPLE 823-(4-{1-[2-(2,6-Dichloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹H NMR (400 MHz, CDCl₃): δ 1.05 (t, 3H, J=6.4 Hz), 1.45 (d, 3H,J=6.8 Hz), 2.80-2.86 (dd, 1H, J=6.9 Hz, 13.7 Hz), 2.97-3.01 (d, 1H,J=13.2 Hz), 3.10-3.18 (m, 2H), 3.22-3.30 (m, 1H), 3.46-3.62 (m, 3H),3.92 (br s, 1H), 4.56 (q, 1H, J=6.4 Hz), 6.71-6.77 (m, 3H), 7.05 (t, 1H,J=7.8 Hz), 7.12 (d, 2H, J=7.8 Hz), 7.22 (d, 2H, J=7.8 Hz); MS (MH+):454.1

EXAMPLE 832-Ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹H NMR (400 MHz, CDCl₃): δ 1.16 (t, 3H, J=6.8 Hz), 1.21 (t, 3H,J=7.6 Hz), 1.49 (d, 3H, J=6.4 Hz), 2.60 (q, 2H, J=6.8 Hz), 2.60-2.68 (m,1H), 2.73-2.80 (m, 1H), 2.94-3.00 (dd, 1H, J=7.8 Hz, 14.2 Hz), 3.04-3.09(dd, 1H, J=4.3 Hz, 14.2 Hz), 3.40-3.46 (m, 2H), 3.52-3.65 (m, 2H), 4.03(dd, 1H, J=4.3 Hz, 7.8 Hz), 4.62 (q, 1H, J=6.8 Hz), 6.52 (t, 1H, J=6.4Hz), 6.76 (d, 2H, J=8.8 Hz), 6.95 (d, 2H, J=7.8 Hz), 7.06 (d, 2H, J=7.8Hz), 7.18 (d, 2H, J=8.3 Hz); MS (MH+): 414.2.

EXAMPLE 842-Ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹H NMR (400 MHz, CDCl₃): δ 0.97 (t, 3H, J=7.8 Hz), 1.19 (t, 3H,J=7.6 Hz), 1.21 (t, 3H, J=6.8 Hz), 1.80-1.90 (m, 1H), 1.90-1.98 (m, 1H),2.60 (q, 2H, J=7.3 Hz), 2.60-2.68 (m, 1H), 2.72-2.79 (m, 1H), 2.99 (dd,1H, J=7.3 Hz, 14.2 Hz), 3.08 (dd, 1H, J=3.9 Hz, 12.7 Hz), 3.40-3.48 (m,2H), 3.52-3.64 (m, 2H), 4.02-4.07 (m, 1H), 4.48 (dd, 1H, J=4.8 Hz, 6.8Hz), 6.54 (t, 1H, J=6.4 Hz), 6.60 (d, 2H, J=8.8 Hz), 6.87 (d, 2H, J=8.3Hz), 6.96 (d, 2H, J=7.8 Hz), 7.02 (d, 2H, J=8.3 Hz); MS (MH+): 428.2.

EXAMPLE 852-Ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-propoxy}-phenyl)-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹H NMR (400 MHz, CDCl₃): δ 0.80 (t, 3H, J=6.8 Hz), 1.03 (t, 3H,J=7.6 Hz), 1.10-1.20 (m, 11H), 2.85-2.89 (m, 1H), 2.91 (dd, 1H, J=7.3Hz, 14.2 Hz), 2.98 (dd, 1H, J=4.8 Hz, 14.2 Hz), 2.96-3.01 (m, 1H),3.37-3.43 (m, 2H), 3.50-3.57 (m, 2H), 3.99 (dd, 1H, J=4.4 Hz, 7.3 Hz),4.52 (t, 1H, J=6.4 Hz), 6.54 (t, 1H, J=6.4 Hz), 6.68 (d, 2H, J=8.3 Hz),7.02 (d, 2H, J=8.3 Hz); MS (MH+): 380.2

EXAMPLE 862-Ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-propoxy}-phenyl)-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹H NMR (400 MHz, CDCl₃, one diastereomer): δ 0.92 (t, 3H, J=7.3Hz), 1.10 (t, 3H, J=6.8 Hz), 1.74-1.82 (m, 1H), 1.86-1.891 (m, 1H),2.56-2.62 (m, 1H), 2.64-2.71 (m, 1H), 2.86 (dd, 1H, J=7.3 Hz, 14.2 Hz),2.98 (dd, 1H, J=4.4 Hz, 14.2 Hz), 3.33-3.40 (m, 2H), 3.49-3.57 (m, 2H),3.95-3.99 (m, 1H), 4.41 (dd, 1H, J=4.4 Hz, 6.8 Hz), 6.40 (t, 1H, J=6.4Hz), 6.70 (d, 2H, J=8.3 Hz), 6.78 (d, 2H, J=8.8 Hz), 6.88-6.94 (m, 4H),7.01-7.06 (m, 1H), 7.08 (d, 2H, J=8.8 Hz), 7.25(d, 1H, J=7.4 Hz), 7.27(d, 1H, J=7.8 Hz); MS (MH+): 492.1.

EXAMPLE 873-(4-{Cyclohexyl-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-2-ethoxy-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹H NMR (400 MHz, CDCl₃): δ 1.16 (t, 3H, J=7.8 Hz), 1.20 (t, 3H,J=7.6 Hz), 1.20-1.30 (m, 6H), 1.49 (d, 3H, J=6.8 Hz), 2.08 (s, 2H), 2.60(q, 2H, J=7.3 Hz), 2.64-2.69 (m, 1H), 2.72-2.80 (m, 1H), 2.97 (dd, 1H,J=6.4 Hz, 14.2 Hz), 3.08 (dd, 1H, J=4.4 Hz, 4.4 Hz), 3.38-3.48 (m, 2H),3.52-3.66 (m, 2H), 3.80-3.90 (m, 1H), 4.02 (dd, 1H, J=4.4 Hz, 7.8 Hz),4.62 (q, 1H, J=6.9 Hz), 4.93-5.02 (m, 1H), 6.53 (t, 1H, J=5.9 Hz), 6.76(d, 2H, J=8.8 Hz), 6.95 (d, 2H, J=8.3 Hz), 7.07 (d, 2H, J=7.8 Hz),7.17(d, 2H, J=8.3 Hz); MS (MH+): 483.2.

EXAMPLE 882-Ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-2-phenyl-ethoxy}-phenyl)-propionicacid

The title compound was prepared using same method for(S,S)-3-(4-{1-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid. ¹H NMR (400 MHz, CDCl₃): δ 1.16 (t, 3H, J=7.8 Hz), 1.21 (t, 3H,J=7.3 Hz), 2.55-2.65 (m, 4H), 2.96 (dd, 1H, J=8.3 Hz, 14.2 Hz), 3.04(dd, 1H, J=3.9 Hz, 14.2 Hz), 3.12 (dd, 1H, J=6.8 Hz, 14.2 Hz), 3.24 (dd,1H, J=3.4 Hz, 14.2 Hz), 3.39-3.45 (m, 3H), 3.59-3.65 (m, 1H), 4.02 (dd,1H, J=4.4 Hz, 7.8 Hz), 4.62 (q, 1H, J=3.4 Hz), 6.40 (t, 1H, J=5.8 Hz),6.69 (d, 2H, J=8.8 Hz), 6.86 (d, 2H, J=7.8 Hz), 7.04 (d, 2H, J=8.3 Hz),7.13 (d, 2H, J=8.8 Hz), 7.20-7.30 (m, 5H); MS (M+H): 491.4.

Preparation 11 2-Bromo-N-[2-(4-phenoxy-phenyl)-ethyl]-acetamide

4-phenoxyphenethylamine (213.28 amu, 2.5 g, 1 eq, 10.8 mmol, 1.09 g/mL,2.3 mL) added to a 3-necked flask. Bromoacetyl bromide (201.86 amu, 1.1eq, 11.8 mmol, 2.4 g, 2.317 g/mL, 1.03 mL), pyridine (79.10 amu, 5 eq,4.27 g, 0.978 g/mL, 54 mmol, 4.4 mL) added along with 50 mL CH₂Cl₂.Reaction stirred for 2 hours at RT. CH₂Cl₂ removed and mixture taken upin 200 mL EtOAc. Organic layer washed with brine and water (200 mLeach). Organics seperated, dried sodium sulfate, and rotovaped to give1.56 g material. MS [EI+] 334 (M+H)⁺, MS [EI−] 332 (M−H)⁺

EXAMPLE 902-Methyl-2-phenoxy-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionicacid

3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester(300.352 amu, 1 eq, 225 mg, 0.76 mmol) added to a 3-necked flask. 20 mLdry dioxane added along with sodium hydride (24 amu, 1.1 eq, 0.82 mmol,20 mg, 33 mg of 60% dispersion in mineral oil). Mixture stirred at RTfor 15 minutes. 2-Bromo-N-[2-(4-phenoxy-phenyl)-ethyl]-acetamide (333.1amu, 250 mg, 1 eq, 0.76 mmol) added and reaction stirred for 6 hours at100 deg C. Reaction mixture added to 200 mL EtOAc. Washed with brine andwater (twice each, 200 mL). Organics dried sodium sulfate andconcentrated to give 250 mg of crude material. Material seperated onchromatatron (10-70% EtOAc/hexanes). Product spot isolated andconcentrated to give 25 mg of desired ethyl ester. Material dissolved in5 mL EtOH. Added to a carousel tube along with 5 mL 5N NaOH. Stirredovernight at 50° C. under nitrogen. Reaction mixture added to 100 mLEtOAc. Acidified with 10 mL concentrated HCl. 100 mL brine added andorganic layer removed. Concentrated to give 20 mL product. MS [EI+] 526(M+H)⁺, MS [EI−] 524 (M−H)⁺

EXAMPLE 912-Phenoxy-2-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-benzyl)-butyricacid

The title compound was prepared using same method for2-Methyl-2-phenoxy-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionicacid from 2-(4-Hydroxy-benzyl)-2-phenoxy-butyric acid ethyl ester

MS [EI+] 540 (M+H)⁺, MS [EI−] 538 (M−H)⁺

EXAMPLE 922-Methyl-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-2-(4-trifluoromethoxy-phenoxy)-propionicacid

The title compound was prepared using same method for2-Methyl-2-phenoxy-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionicacid from3-(4-Hydroxy-phenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionicacid ethyl ester.

MS [EI+] 610 (M+H)⁺, MS [EI−] 608 (M−H)⁺

EXAMPLE 932-(4-Fluoro-phenoxy)-2-methyl-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionicacid

The title compound was prepared using same method for2-Methyl-2-phenoxy-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionicacid from 2-(4-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionicacid ethyl ester.

MS [EI+] 544 (M+H)⁺, MS [EI−] 542 (M−H)⁺

EXAMPLE 94(2S)-2-methoxy-3-(4-{2-oxo-2-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethoxy}-phenyl)-propionicacid

Step 1: (2S)-3-(4-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionicacid ethyl ester

The compound of (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ester(Preparation 1), (1.2 g, 5.3 mmol) was dissolved in 25 ml of anhydrousTHF and NaH (380 mg, 15.8 mmol) was added portion wise. After about 5minutes, bromo-acetic acid tert-butyl ester was added dropwise at roomtemperature. The mixture was stirred for 2 hours at room temperature.The crude was dissolved in ethyl acetate (100 ml) and a solution of 5%HCl was added. The mixture was extracted with ethyl acetate (3×100 ml),and the combined organic layers were dried over (MgSO₄) and thenconcentrated under vacuum. The crude was purified by columnchromatography (silica gel, hexane/ethyl acetate 8.5:1,5) to afford ayellow oil.

Step 2: (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethylester

The compound of(2S)-3-(4-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acidethyl ester (PREPARATION 3, step 1) (1.2 gr, 3.5 mmol) was solved indichloromethane (5 ml) and trifluoroacetic acid was added (5 ml). Themixture was stirred for an hour, and the crude was concentrated toafford a yellow oil. ¹H-NMR (CDCl₃, 200.15 MHz): 7.16 (d, 2H, J=8.3),6.75 (d, 2H, J=8.3), 4.89 (s, 2H), 4.14 (c, 2H, J=6.9), 3.94 (t, 1H,J=6.9), 3.57 (dc, 1H), 3.35 (dc, 1H), 2.92 (d, 2H, J=6.9), 1.23-1.10(2t, 6H).

Step 3:(2S)-2-methoxy-3-(4-{2-oxo-2-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-(4-trifluoromethyl-phenyl)-piperazine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₃H₂₅F₃NO₅ [M+H]⁺: 467.

EXAMPLE 95(2S)-3-(4-{[(biphenyl-4-ylmethyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and C-biphenyl-4-yl-methylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₅H₂₅NO₅ [M+H]⁺: 420.

EXAMPLE 96(2S)-2-methoxy-3-{4-[(methyl-naphthalen-1-ylmethyl-carbamoyl)-methoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and methyl-naphthalen-1-ylmethyl-amine via thesame procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₂₅NO₅ [M+H]⁺: 408.

EXAMPLE 97(2S)-3-{4-[2-(4-benzhydryl-piperazin-1-yl)-2-oxo-ethoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-benzhydryl-piperazine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₉H₃₂N₂O₅ [M+H]⁺: 489.

EXAMPLE 98(2S)-3-[4-(2-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-oxo-ethoxy)-phenyl]-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-[bis-4-fluoro-phenyl)-methyl]-piperazinevia the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₉H₃₀F₂N₂O₅ [M+H]⁺: 525.

EXAMPLE 99(2S)-2-methoxy-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 2-(4-phenoxy-phenyl)-ethylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₆H₂₇NO₆ [M+H]⁺: 450.

EXAMPLE 100(2S)-3-{4-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1,2,3,4-tetrahydro-isoquinoline via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a yellow oil. MS (ES) for C₂₁H₂₃NO₅[M+H]⁺: 370.

EXAMPLE 101(2S)-3-{4-[(benzyl-phenethyl-carbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and benzyl-phenethyl-amine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a yellow oil. MS (ES) for C₂₇H₂₉NO₅[M+H]⁺: 448.

EXAMPLE 102(2S)-3-(4-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-(4-fluoro-phenyl)-piperazine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₅FN₂O₅ [M+H]⁺: 417.

EXAMPLE 103(2S)-2-methoxy-3-4-{[2-(2-methoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-(4-chloro-phenyl)-2-methyl-piperazine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a yellow oil. MS (ES) forC₂₃H₂₇ClN₂O₅ [M+H]⁺: 447.

EXAMPLE 104(2S)-3-(4-{2-[4-(3-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-(3-chloro-phenyl)-piperazine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a yellow oil. MS (ES) forC₂₂H₂₅ClN₂O₅ [M+H]⁺: 433.

EXAMPLE 105(2S)-3-(4-{2-[4-(4-chloro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-(4-chloro-benzyl)-piperazine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₃H₂₇ClN₂O₅ [M+H]⁺: 447.

EXAMPLE 106(2S)-3-(4-{2-[4-(2-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-(2-fluoro-phenyl)-piperazine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a yellow oil. MS (ES) forC₂₂H₂₅FN₂O₅ [M+H]⁺: 417.

EXAMPLE 106A(2S)-3-(4-{[(benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and C-benzo[1,3]dioxol-5-yl-methylamine via thesame procedure used for the preparation of(2S,1R)-2-Ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₀H₂₁NO₇ [M+H]⁺: 388.

EXAMPLE 106B(2S)-3-(4-{[2-(4-bromo-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 2-(4-bromo-phenyl)-ethylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₀H₂₂BrNO₅ [M+H]⁺: 437.

EXAMPLE 107(2S)-2-methoxy-3-(4-{[(naphthalen-1-ylmethyl)-carbamoyl]-methoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and C-naphthalen-1-yl-methylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₃H₂₃NO₅ [M+H]⁺: 394.

EXAMPLE 108(2S)-3-(4-{[2-(2,6-dichloro-benzylsulfanyl)-ethylcarbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and C-naphthalen-1-yl-methylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a yellow oil. MS (ES) forC₂]H₂₃Cl₂NO₅S [M+H]⁺: 473.

EXAMPLE 109(2S)-3-(4-{[benzyl-(1-phenyl-ethyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and(1-phenyl-ethyl)-(2-vinyl-hexa-2,4-dienyl)-amine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₇H₂₉NO₅ [M+H]⁺: 448.

EXAMPLE 110(2S)-3-(4-{2-[4-(4-acetyl-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-(4-piperazin-1-yl-phenyl)-ethanone via thesame procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₄H₂₈N₂O₆ [M+H]⁺: 441.

EXAMPLE 111(2S)-2-methoxy-3-{4-[2-oxo-2-(4-p-tolyl-piperazin-1-yl)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-p-tolyl-piperazine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a yellow oil. MS (ES) for C₂₃H₂₈N₂O₅[M+H]⁺: 413.

EXAMPLE 112(2S)-3-(4-{[ethyl-(2-fluoro-benzyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and ethyl-(2-fluoro-benzyl)-amine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₁H₂₄FNO₅ [M+H]⁺:390.

EXAMPLE 113(2S)-3-(4-{[ethyl-(3-methyl-benzyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and ethyl-(3-methyl-benzyl)-amine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₇NO₅ [M+H]⁺: 386.

EXAMPLE 114(2S)-3-(4-{2-[4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-ropionic acid ethyl ester(PREPARATION 3, step 2) and 1-(4-fluoro-benzyl)-piperazine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₃H₂₇FN₂O₅ [M+H]⁺: 431.

EXAMPLE 115(2S)-3-{4-[(6-fluoro-benzothiazol-2-ylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 6-fluoro-benzothiazol-2-ylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₉H₁₇FN₂O₅S [M+H]⁺: 405.

EXAMPLE 116(2S)-3-(4-{[2-(ethyl-m-tolyl-amino)-ethylcarbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and N1-ethyl-N1-m-tolyl-ethane-1,2-diamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₃H₃₀N₂O₅ [M+H]⁺: 414.

EXAMPLE 117(2S)-2-methoxy-3-{4-[(2-pyridin-2-yl-ethylcarbamoyl)-methoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 2-pyridin-2-yl-ethylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₉H₂₂N₂O₅ [M+H]⁺: 359.

EXAMPLE 118(2S)-2-methoxy-3-{4-[(2-pyridin-3-yl-ethylcarbamoyl)-methoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 2-pyridin-3-yl-ethylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₉H₂₂N₂O₅ [M+H]⁺: 359.

EXAMPLE 119(2S)-E-3-{4-[(4-tert-butyl-cyclohexylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and E-4-tert-butyl-cyclohexylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₃₃NO₅ [M+H]⁺: 392.

EXAMPLE 120(2S)-Z-3-{4-[(4-tert-butyl-cyclohexylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and Z-4-tert-butyl-cyclohexylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₃₃NO₅ [M+H]⁺: 392.

EXAMPLE 121(2S)-3-(4-cyclobutylcarbamoylmethoxy-phenyl)-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and cyclobutylamine via the same procedure usedfor the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₆H₂₁NO₅ [M−H]⁻: 306.

EXAMPLE 122(2S)-3-{4-[(1,3-dimethyl-butylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1,3-dimethyl-butylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₈H₂₇NO₅ [M−H]⁻: 336.

EXAMPLE 123(2S)-2-methoxy-3-{4-[(1-methyl-hexylcarbamoyl)-methoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-methyl-hexylamine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₉H₂₉NO₅ [M−H]⁻: 350.

EXAMPLE 124(2S)-2-methoxy-3-{4-[(1-methyl-butylcarbamoyl)-methoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-methyl-butylamine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₇H₂₅NO₅ [M−H]⁻: 322.

EXAMPLE 125(2S)-2-methoxy-3-{4-[(3-methyl-butylcarbamoyl)-methoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 3-methyl-butylamine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₇H₂₅NO₅ [M−H]⁻: 322.

EXAMPLE 126(2S)-3-(4-cyclopentylcarbamoylmethoxy-phenyl)-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and cyclopentylamine via the same procedure usedfor the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₇H₂₃NO₅ [M−H]⁻: 320.

EXAMPLE 127(2S)-2-methoxy-3-{4-[(1-methyl-3-phenyl-propylcarbamoyl)-methoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 1-methyl-3-phenyl-propylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₂₇NO₅ [M−H]⁻: 384.

EXAMPLE 128(2S)-3-{4-[(2,2,3,3,4,4,4-heptafluoro-butlcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and nonafluorobutylamine via the same procedureused for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₆H₁₆F₇NO₅ [M−H]⁻: 434.

EXAMPLE 129(2S)-3-{4-[(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 5-tert-butyl-[1,3,4]thiadiazol-2-ylamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₈H₂₃N₃O₅S [M−H]⁻: 392.

EXAMPLE 130(2S)-3-{4-[(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 5-tert-butyl-[1,3,4]thiadiazol-2-ylamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₈H₂₃N₃O₅S [M−H]⁻: 392.

EXAMPLE 131(2S)-3-{4-[(4-tert-butyl-thiazol-2-ylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 4-tert-butyl-3H-114-thiazol-2-ylamine viathe same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₉H₂₄N₂O₅S [M−H]⁻: 391.

EXAMPLE 1323-{4-[(5-cyclopropyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 5-cyclopropyl-[1,3,4]thiadiazol-2-ylaminevia the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₇H₁₉N₃O₅S [M−H]⁻: 376.

EXAMPLE 133 (2S)-3-(4-hexylcarbamoylmethoxy-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and hexylamine via the same procedure used forthe preparation of(2S,1R)-2-Ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₈H₂₇NO₅ [M−H]⁻: 338.

EXAMPLE 134 (2S)-3-(4-heptylcarbamoylmethoxy-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and heptylamine via the same procedure used forthe preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₉H₂₉NO₅ [M−H]⁻: 352.

EXAMPLE 135(2S)-3-{4-[(3,3-dimethyl-butylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester(PREPARATION 3, step 2) and 3,3-dimethyl-butylamine via the sameprocedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₁₈H₂₇NO₅ [M−H]⁻: 338.

EXAMPLE 1363-{3-[(4-cis-tert-butyl-cyclohexylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid (isomer 1)

The title compound was prepared from3-(3-carboxymethoxy-phenyl)-2-methoxy-propionic acid methyl ester(PREPARATION 4, step 2) and 4-cis-tert-butyl-cyclohexylamine via thesame procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₃₃NO₅ [M+H]⁺: 392.

EXAMPLE 1373-{3-[(4-trans-tert-butyl-cyclohexylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid (isomer 2)

The title compound was prepared from3-(3-carboxymethoxy-phenyl)-2-methoxy-propionic acid methyl ester(PREPARATION 4, step 2) and 4-trans-tert-butyl-cyclohexylamine via thesame procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil. MS (ES) forC₂₂H₃₃NO₅ [M+H]⁺: 392.

EXAMPLE 1383-(4-heptylcarbamoylmethoxy-phenyl)-2-methoxy-2-methyl-propionic acid

The title compound was prepared from3-(4-carboxymethoxy-phenyl)-2-methoxy-2-methyl-propionic acid methylester heptyl amine via the same procedure used for the preparation of(2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid (Example 1, step 3) to produce a colorless oil.

MS (ES) for C₂₀H₃₁NO₅ [M+H]⁺: 366.

EXAMPLE 139

EXPERIMENTALS

Procedure: Compound 1 (204 g, 1 mole) and sodium iodide (375 g, 2.5mole) was dissolved in 1 L of concentrated hydrochloric acid at ambienttemperature. The solution was heated to reflux for 6 hr and then cooledin an ice-water bath for 2 hr. The slurry was filtered and the filtercake was washed with 300 ml cold water. The white solid was collectedand dried in a vacuum oven at 60° C. to provide 178.7 g crude solid. Thecrude solid was stirred in 2 L of acetonitrile for 1 hr at ambienttemperature. The solution was filtered and the filtrate was concentratedunder vacuum to provide 123 g of Compound 2 as an off-white solid.

Synthesis of Compound 3

To the solution of Compound 2 (43.32, 0.238 mole) in absolute ethanol(950 mL) was added K₂CO₃ (65.73 g, 0.476 mole) and the benzyl chloride(55 mL, 0.476 mole). The suspension was refluxed for 12 hours and turnedinto a slurry suspension. Then ethanol was removed (65% of the totalquantity), water (1 L) and sodium hydroxide (44 mL) were added untilpH=13-14 in order to hydrolyse the ethyl ester formed during thereaction. After 2 h, the hydrolysis was complete.

The rest of ethanol was removed before the second addition of water (500mL). Then the aqueous phase was extracted twice with diethylether (1000mL) before acidifying dropwise with HCl 37% (88 mL). At this moment ayellow precipitate and an emission of CO₂ were observed. The solid wasfiltered, rinsed with water (500 mL) and dried overnight under reducedpressure at 50° C. to give COMPOUND 3 as an off white solid (60.81 g,94%).

Synthesis of Compound 4

The solid starting material COMPOUND 3 (20 g, 73.5 mmol) is suspended in400 ml of isopropanol and 2.2 ml of H₂SO₄ (41.3 mmol) is added. After 1hour of stirring at RT, we didn't observe any dissolution of theproduct. The mixture is then heated at 43° C. overnight. The HPLC showed11% (area) of remaining starting material. We added 300 ml of tolueneand 200 ml of NaHCO₃ (saturated solution). The layers are separated, theorganic one is dried over MgSO4 followed by a filtration and theevaporation on a rotavapor. We obtained 17.1 g of crude product which is94% (HPLC area) of the desired COMPOUND 4 (yield: 74%).

The product is dissolved in toluene, filtered to clarify the solutionand azeotroped twice with toluene before use in the following step.

Synthesis of Compound 5

Charge in a carefully dried and inerted 6 L reactor COMPOUND 4 (105 g;0,334 moles) and 1000 ml anhydrous DMF. Cool the so obtained solutiondown to −30° C. Add at −30° C. ethyl iodide (261 g; 1,674 moles) andstart than addition over 45′ of a 1M solution of sodium t-amylate intoluene (420 ml; 0.42 moles) keeping T° at −27° C. to −30° C. Reactionmixture gradually changes to a suspension. After 1.5H stirring at −30°C., in-process control still indicates presence of 6% COMPOUND 4. Anadditional portion of 1M sodium t-amylate (30 ml, 0.03 moles) is thanadded and reaction mixture stirred 1H. Acetic acid (32.5 g; 1.54 moles)is than added drop-wise and temperature allowed to increase to roomtemperature. 2 L toluene are than added and 1.5 L DI water added at 10°C. (exothermic dissolution with temperature increasing up to 22° C.).The upper organic layer is isolated and the lower aqueous layer isdiluted with 0.5 L water and re-extracted by 0.5 L toluene. The combinedorganic layers are washed twice with 0.5 L DI water and once with 15%NaCl solution. Solvent is than evaporated under reduced pressure up to50° C. in order to isolate 111.9 g crude COMPOUND 5.

Crude material is than purified on 330 g silica using acyclohexane/ethyl acetate 90/10 mixture as eluent. Purified COMPOUND 5is isolated as a pale yellow oil, with a 90% molar yield (122.8 g; 0.3moles).

Synthesis of Compound 6

Charge in a dried and inertised 2 L Parr hydrogenator Pd/C 10% anhydrous(8 g) and add COMPOUND 5 (80 g; 0.232 moles) dissolved in 800 mlabsolute ethanol. Purge 5× with 1.5 bar Nitrogen and set under 40 PSIhydrogen pressure keeping the temperature lower than 27° C. When no moreHydrogen uptake is observed, In process sample is taken and reactionmixture is filtred on 20 g celite. Pd/C cake is rinsed twice with 50 mlethanol, and combined solutions are concentrated under reduced pressureup to 50° C. Fresh 200 ml toluene are than added and distilled under 80mbar at about 40° C. in order to strip out the residual ethanol. Whennearly completed, distillation of the solvent is then persued at 50° C.down to 10 mbar pressure. LY2195369 is isolated as a yellowish oil (59.7g, 0.236 moles, 100% molar yield) and stored under nitrogen andprotected from light.

Synthesis of Compound 7

A 250 ml Schlenk flask equipped with a condenser and a magnetic stirreris flushed under nitrogen. This system is dried with the heat gun.

The flask is loaded with fresh cut pieces of Na (1.4 g, 60.9 mmol, 3.0eq). The starting material (5.1 g; 20.21 mmol; 1.0 eq.) is loaded with100 ml of anhydrous THF. The flask that contained the starting materialis rinsed with 50 ml of anhydrous THF and also adding to the reactionvessel. We immediately observed a gas evolution started on the Nasurface that has a metallic aspect. The brownish red mixture is stirredat ambient temperature for 1 hour.

The chloropropionic acid (1.86 ml; 21.2 mmol, 1.05 eq, 1% H₂O by KF) isadded neat dropwise. The sodium surface cleaned again and about halfwaytrough the addition a gel formed at the top of the reaction mixture.However the bottom portion is stirred without trouble. The mixture isheated in a 55° C. oil bath; the gel can be broken, the stirring is noweasy and the addition is accomplished.

The evolution of the reaction is controlled by HPLC. The reactionmixture is heated at about 50° C. during 5 hours for an almost completeconversion of the starting material. The mixture is cooled to RT andpoured on 130 ml of a 5% aqueous solution of NaH₂PO₄ (pH=4.15). The pHafter the quench is 5.8. We added 75 ml of toluene and the pH of theaqueous layer is adjusted to 2.15 with 6.5 ml of 6N HCl. By this way,all the products go to the organic layer. The layers are separated, theorganic one is concentrated on a rotavapor to give 7.4 g of a crude oil(90.3 area % of the desired compound). The aqueous layer contains noproducts.

The crude oil (7.4 g) is taken in 50 ml of toluene and washed withaqueous saturated NaHCO₃ solution (2×50 ml) to remove unreacted SM. ThepH of the aqueous layer is 8.3. Fresh toluene (75 ml) is added and themixture is acidified with 6 N HCl (20 ml) to pH=2.5.

The layers are separated and the organic one is evaporated on arotavapor to get 6 g of an oil with a crude yield of 92%.

Biological Assays

Binding and Cotransfection Studies

The in vitro potency of compounds in modulating PPARγ and PPARαreceptors are determined by the procedures detailed below. DNA-dependentbinding (ABCD binding) is carried out using SPA technology with PPARreceptors. Tritium-labeled PPARα and PPARγ agonists are used asradioligands for generating displacement curves and IC₅₀ values withcompounds of the invention. Cotransfection assays are carried out inCV-1 cells. The reporter plasmid contains an acylCoA oxidase (AOX) PPREand TK promoter upstream of the luciferase reporter cDNA. AppropriatePPARs and RXRα are constitutively expressed using plasmids containingthe CMV promoter. For PPARα and PPARβ, interference by endogenous PPARγin CV-1 cells is an issue. In order to eliminate such interference, aGAL4 chimeric system is used in which the DNA binding domain of thetransfected PPAR is replaced by that of GAL4, and the GAL4 responseelement is utilized in place of the AOX PPRE. Cotransfection efficacy isdetermined relative to PPARα agonist and PPARγ agonist referencemolecules. Efficacies are determined by computer fit to aconcentration-response curve, or in some cases at a single highconcentration of agonist (10 μM). For binding or cotransfection studieswith receptors other than PPARs, similar assays are carried out usingappropriate ligands, receptors, reporter constructs, etc., for thatparticular receptor.

These studies are carried out to evaluate the ability of compounds ofthe invention to bind to and/or activate various nuclear transcriptionfactors, particularly huPPARα (“hu” indicates “human”) and huPPARγ.These studies provide in vitro data concerning efficacy and selectivityof compounds of the invention. Furthermore, binding and cotransfectiondata for compounds of the invention are compared with corresponding datafor marketed compounds that act on either huPPARα or huPPARγ.

Binding and cotransfection data for representative compounds of theinvention are compared with corresponding data for reference todetermine the binding.

The binding and cotransfection efficacy values found, for compounds ofthis invention which are useful for modulating a PPAR alpha receptor,are about ≦100 nM and ≧50%, respectively. When coagoanist modulators aredesired, the values may be balanced against selectivity for the gamma oranother desired PPAR receptor subtype.

Evaluation of Triglyceride Reduction and HDL Cholesterol Elevation inHuapoAI

Transgenic Mice

Seventeen different series of studies are performed to evaluate theeffect of compounds of the present invention upon HDL and triglyceridelevels in human apoAI mice. For each compound tested, seven to eightweek old male mice, transgenic for human apoAI (for example,C57BL/6-tgn(apoa1)1rub, Jackson Laboratory, Bar Harbor, Me.) areacclimated in individual cages for two weeks with standard chow diet andwater provided ad libitum. After the acclimation, mice and chow areweighed and assigned to test groups (n=5) with randomization by bodyweight. Mice are dosed daily by oral gavage for 8 days using a 29 gauge,1½ inch curved feeding needle. The vehicle for the controls, testcompounds and the positive control is 1% carboxymethylcellulose (w/v)with 0.25% tween 80 (w/v). All mice are dosed daily between 6 and 8 a.m.with a dosing volume of 0.2 ml. Prior to termination, animals and dietsare weighed and body weight change and food consumption are calculated.Three hours after last dose, mice are euthanized with CO2 and blood isremoved (0.5-1.0 ml) by cardiac puncture. After sacrifice, the liver,heart, and epididymal fat pad are excised and weighed. Blood ispermitted to clot and serum is separated from the blood bycentrifugation.

Cholesterol and triglycerides are measured colorimetrically usingcommercially prepared reagents (for example, as available from Sigma#339-1000 and Roche #450061 for triglycerides and cholesterol,respectively). The procedures are modified from published work (see,McGowan M. W. et al., Clin Chem 29:538-542, 1983; Allain C. C. et al.,Clin Chem 20:470-475, 1974. Commnercially available standards fortriglycerides and total cholesterol, respectively, commercial qualitycontrol plasma, and samples are measured in duplicate using 200 μl ofreagent. An additional aliquot of sample, added to a well containing 200μl water, provides a blank for each specimen. Plates are incubated atroom temperature on a plate shaker and absorbance is read at 500 nm and540 nm for total cholesterol and triglycerides, respectively. Values forthe positive control are always within the expected range and thecoefficient of variation for samples is below 10%. All samples from anexperiment are assayed at the same time to minimize inter-assayvariability.

Serum lipoproteins are separated and cholesterol quantitated by fastprotein liquid chromatography (FPLC) coupled to an in line detectionsystem. Cholesterol reagent (Roche Diagnostics Chol/HP 704036) is elutedat 0.16 ml/min mixed with the column effluent through a T-connection andthe mixture passed through a 15 m×0.5 mm id knitted tubing reactorimmersed in a 37 C water bath. The colored product produced in thepresence of cholesterol is monitored in the flow strem at 505 nm and theanalog voltage from the monitor is converted to a digital signal forcollection and analysis. The change in voltage corresponding to changein cholesterol concentration is plotted vs time and the area under thecurve corresponding to the elution of very low density lipoprotein(VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL)is calculated using Perkin Elmer Turbochrome software.

Triglyceride Serum Levels in mice dosed with a Compound of the Inventionis compared to mice receiving the vehicle to identify compounds whichcould be particularly useful for lowering triglycerides. Generally,triglyceride decreases of greater than or equal to 30% (thirty percent)compared to control following a 30 mg/kg dose suggests a compound thatcan be especially useful for lowering triglyceride levels.

The percent increase of HDLc serum levels in mice receiving a compoundof the invention is compared to mice receiving vehicle to identifycompounds of the invention that could be particularly useful forelevating HDL levels. Generally, an increase of greater than or equal to25% (twenty five percent) increase in HDLc level following a 30 mg/kgdose suggests a compound that can be especially useful for elevatingHDLc levels.

It may be particularly desirable to select compounds of this inventionthat both lower triglyceride levels and increase HDLc levels. However,compounds that either lower triglyceride levels or increase HDLc levelsmay be desirable as well.

Evaluation of Glucose Levels in db/db Mice

The effects, upon plasma glucose of administering various dose levels offive different compounds of the present invention and a known PPAR gammaagonist or a known PPAR alpha agonist, and the control, to male db/dbmice, are studied.

Five week old male diabetic (db/db) mice [for example, C57BlKs/j-m +/+Lepr(db), Jackson Laboratory, Bar Harbor, Me.] or lean littermates arehoused 6 per cage with food and water available at all times. After anacclimation period of 2 weeks, animals are individually identified byear notches, weighed, and bled via the tail vein for determination ofinitial glucose levels. Blood is collected (100 μl) from unfastedanimals by wrapping each mouse in a towel, cutting the tip of the tailwith a scalpel, and milking blood from the tail into a heparinizedcapillary tube. Sample is discharged into a heparinized microtainer withgel separator and retained on ice. Plasma is obtained aftercentrifugation at 4° C. and glucose measured immediately. Remainingplasma is frozen until the completion of the experiment, when glucoseand triglycerides are assayed in all samples. Animals are grouped basedon initial glucose levels and body weights. Beginning the followingmorning, mice are dosed daily by oral gavage for 7 days. Treatments aretest compounds (30 mg/kg), a positive control agent (30 mg/kg) orvehicle [1% carboxymethylcellulose (w/v)/0.25% Tween80 (w/v); 0.3ml/mouse]. On day 7, mice are weighed and bled (tail vein) 3 hours afterdosing. Twenty-four hours after the 7^(th) dose (i.e., day 8), animalsare bled again (tail vein). Samples obtained from conscious animals ondays 0, 7 and 8 are assayed for glucose. After the 24 hour bleed,animals are weighed and dosed for the final time. Three hours afterdosing on day 8, animals are anesthetized by inhalation of isofluraneand blood obtained via cardiac puncture (0.5-0.7 ml). Whole blood istransferred to serum separator tubes, chilled on ice and permitted toclot. Serum is obtained after centrifugation at 4° C. and frozen untilanalysis for compound levels. After sacrifice by cervical dislocation,the liver, heart and epididymal fat pads are excised and weighed.

Glucose is measured calorimetrically using commercially purchasedreagents. According to the manufacturers, the procedures are modifiedfrom published work (see, McGowan, M. W., Artiss, J. D., Strandbergh, D.R. & Zak, B. Clin Chem, 20:470-5 (1974) and Keston, A. Specificcolorimetric enzymatic analytical reagents for glucose. Abstract ofpapers 129th Meeting ACS, 31C (1956).); and depend on the release of amole of hydrogen peroxide for each mole of analyte, coupled with a colorreaction first described by Trinder (Trinder, P. Determination ofglucose in blood using glucose oxidase with an alternative oxygenacceptor. Ann Clin Biochem, 6:24 (1969)). The absorbance of the dyeproduced is linearly related to the analyte in the sample. The assaysare further modified in our laboratory for use in a 96 well format. Thecommercially available standard for glucose, commercially availablequality control plasma, and samples (2 or 5 μl/well) are measured induplicate using 200 μl of reagent. An additional aliquot of sample,pipetted to a third well and diluted in 200 μl water, provided a blankfor each specimen. Plates are incubated at room temperature for 18minutes for glucose on a plate shaker and absorbance is read at 500 nmon a plate reader. Sample absorbances are compared to a standard curve(100-800 for glucose). Values for the quality control sample are alwayswithin the expected range and the coefficient of variation for samplesis below 10%. All samples from an experiment are assayed at the sametime to minimize inter-assay variability.

The results of the study, suggest compounds of the present inventionthat significantly reduce db/db mouse plasma glucose levels whileresulting in body weight gains that are less than those observed for aknown standard.

Evaluation of the Effects of Compounds of the Present Invention uponA^(y) Mice Body Weight Fat Mass Glucose and Insulin Levels

Female A^(y) Mice

Female A^(y) mice are singly housed, maintained under standardizedconditions (22° C., 12 h light:dark cycle), and provided free access tofood and water throughout the duration of the study. At twenty weeks ofage the mice are randomly assigned to vehicle control and treated groupsbased on body weight and body fat content as assessed by DEXA scanning(N=6). Mice are then dosed via oral gavage with either vehicle or aCompound of this invention (50 mg/kg) one hour after the initiation ofthe light cycle (for example, about 7 A.M.) for 18 days. Body weightsare measured daily throughout the study. On day 14 mice are maintainedin individual metabolic chambers for indirect calorimetry assessment ofenergy expenditure and fuel utilization. On day 18 mice are againsubjected to DEXA scanning for post treatment measurement of bodycomposition.

The results of p.o. dosing of compound for 18 days on body weight, fatmass, and lean mass are evaluated and suggest which compounds of thisinvention can be especially useful for maintaining desirable weightand/or promoting desired lean to fat mass.

Indirect calorimetry measurements revealed a significant reduction inrespiratory quotient (RQ) in treated animals during the dark cycle[0.864±0.013 (Control) vs. 0.803±0.007 (Treated); p<0.001]. Thisreduction in RQ is indicative of an increased utilization of fat duringthe animals' active (dark) cycle. Additionally, treated animals displaysignificantly higher rates of energy expenditure than control animals(17.40±0.49 vs. 13.62±0.26 kcal/kg/hr, respectively).

Male KK/A^(y) Mice

Male KK/A^(y) mice are singly housed, maintained under standardizedconditions (22° C., 12 h light:dark cycle), and provided free access tofood and water throughout the duration of the study. At twenty-two weeksof age the mice are randomly assigned to vehicle control and treatedgroups based on plasma glucose levels. Mice are then dosed via oralgavage with either vehicle or a Compound of this invention (30 mg/kg)one hour after the initiation of the light cycle (7 A.M.) for 14 days.Plasma glucose, triglyceride, and insulin levels are assessed on day 14.

The results of p.o. dosing of compound for 14 days on plasma glucose,triglycerides, and insulin are evaluated to identify compounds of thisinvention that may be especially desired.

Method to Elucidate the LDL-Cholesterol Total-Cholesterol andTriglyceride Lowering Effect of Compound 5(8)

Male Syrian hamsters (Harlan Sprague Dawley) weighing 80-120 g areplaced on a high-fat cholesterol-rich diet for two to three weeks priorto use. Feed and water are provided ad libitum throughout the course ofthe experiment. Under these conditions, hamsters becamehypercholesterolemic showing plasma cholesterol levels between 180-280mg/dl. (Hamsters fed with normal chow had a total plasma cholesterollevel between 100-150 mg/dl.) Hamsters with high plasma cholesterol (180mg/dl and above) are randomized into treatment groups based on theirtotal cholesterol level using the a commercially available program.

A Compound of this invention is dissolved in an aqueous vehicle(containing CMC with Tween 80) such that each hamster receives once aday approx. 1 ml of the solution by garvage at doses 3 and 30 mg/kg bodyweight. Fenofibrate (Sigma Chemical, prepared as a suspension in thesame vehicle) is given as a known alpha-agonist control at a dose of 200mg/kg, and the blank control is vehicle alone. Dosing is performed dailyin the early morning for 14 days.

Quantification of Plasma Lipids:

On the last day of the test, hamsters are bled (400 ul) from thesuborbital sinus while under isoflurane anesthesia 2 h after dosing.Blood samples are collected into heparinized microfuge tubes chilled inice bath. Plasma samples are separated from the blood cells by briefcentrifugation. Total cholesterol and triglycerides are determined bymeans of enzymatic assays carried out automatically in the Monarchequipment (Instrumentation Laboratory) following the manufacturer'sprecedure. Plasma lipoproteins (VLDL, LDL and HDL) are resolved byinjecting 25 ul of the pooled plasma samples into an FPLC system elutedwith phosphate buffered saline at 0.5 ml/min through a 6 HR 10/30 columnmaintained room temp. Detection and characterization of the isolatedplasma lipids are accomplished by postcolumn incubation of the effluentwith a Cholesterol/HP reagent (for example, Roche Lab System; infused at0.12 ml/min) in a knitted reaction coil maintained at 37° C. Theintensity of the color formed is proportional to the cholesterolconcentration and is measured photometrically at 505 nm.

The effect of administration of a Compound of this invention for 14 daysis studied for the percent reduction in LDL level with reference to thevehicle group. The LDL-lowering efficacy for especially desiredcompounds of this invention is markedly more potent than that offenofibrate. Compounds of this invention that decrease LDL greater thanor equal to 30% (thirty percent) compared to vehicle can be especiallydesired.

The total-cholesterol and triglyceride lowering effects of a Compound ofthis invention is also studied. The data for reduction in totalcholesterol and triglyceride levels after treatment with a compound ofthis invention for 14 days is compared to the vehicle to suggestcompounds that can be particularly desired. The effect of the knowncontrol is measured.

Method to Elucidate the Fibrinogen-Lowering Effect of PPARModulators

Zucker Fatty Rat Model:

The life phase of the study on fibrinogen-lowering effect of compoundsof this invention is part of the life phase procedures for theantidiabetic studies of the same compounds. On the last (14^(th)) day ofthe treatment period, with the animals placed under surgical anesthesia,˜3 ml of blood is collected, by cardiac puncture, into a syringecontaining citrate buffer. The blood sample is chilled and centrifugedat 4° C. to isolate the plasma that is stored at −70° C. prior tofibrinogen assay.

Quantification of Rat Plasma Fibrinogen:

Rat plasma fibrinogen levels are quantified by using a commercial assaysystem consists of a coagulation instrument following the manufacturer'sprotocol. In essence, 100 ul of plasma is sampled from each specimen anda 1/20 dilution is prepared with buffer. The diluted plasma is incubatedat 37° C. for 240 seconds. Fifty microliters of clotting reagentthrombin solution (provided by the instrument's manufacturer in astandard concentration) is then added. The instrument monitors theclotting time, a function of fibrinogen concentration quantified withreference to standard samples.

Results:

Compounds of this invention may be capable of lowering fibrinogen levelin vivo. Compounds that lower fibrinogen level greater than vehicle canbe especially desired.

Cholesterol and triglyceride lowering effects of compounds of thisinvention may also produced in Zucker rats.

Method to Elucidate the Anti-Body Weight Gain and Anti-Appetite Effectsof Compounds of this Invention

Fourteen-Day Study in Zucker Fatty Rat¹ or ZDF Rat² Models:

Male Zucker Fatty rats, non-diabetic (Charles River Laboratories,Wilmington, Mass.) or male ZDF rats (Genetic Models, Inc, Indianapolis,Ind.) of comparable age and weight are acclimated for 1 week prior totreatment. Rats are on normal chow and water is provided ad libitumthroughout the course of the experiment.

α-agonists are dissolved in an aqueous vehicle such that each ratreceived once a day approximately 1 ml of the solution by garvage atdoses 0.1, 0.3, 1 and 3 mg/kg body weight. Fenofibrate (Sigma Chemical,prepared as a suspension in the same vehicle) a known alpha-agonistgiven at doses of 300 mg/kg, as well as the vehicle are controls. Dosingis performed daily in the early morning for 14 days. Over the course ofthe experiment, body weight and food consumption are monitored. Usingthis assay, compounds of this invention can be identified that can beespecially desired and may result in significant weight reduction.

Certain Features of the present invention may be preferred forpharmaceutical use. The following embodiments of the present inventionand characteristics of compounds within the scope of the presentinvention are listed in tabular form and one or more may beindependently combined to provide a variety of desired compounds andembodiments of the present invention. The following tabular list ofembodiments is illustrative of the present invention and is in no wayintended to limit the scope of the claimed invention.

A) A compound of the formula:

B) A compound of the formula:

C) A compound of the formula:

D) A compound of the formula:

E) R2 is selected from the group consisting of

F) R2 is —CH(C(O)OCH₃)benzyl;

G) R6 is selected from the group consisting of hydrogen, C₁-C₄ alkl andaryl-C₀₋₄-alkyl, and which C₁-C₄ alkl and aryl-C₀₋₄-alkyl are eachindependently substituted with a group selected from R5′;

H) R2 is arylalkyl wherein the aryl is phenyl and the alkyl is C2-C3alkyl, and the phenyl is substituted with from one to three groups eachindependently selected from R2′;

I) R1 is hydrogen;

J) R2 is aryl(C₂-C₃)alkyl which is unsubstituted or substituted withfrom one to three substituents each independently selected from R2′;

K) R2 is arylalkyl substituted by C1-C2 alkyl;

L) R5 is H or methyl.

-   -   M) A compound of the formula:

N) R6 is C₁-C₃ alkyl;

O) R6 is methyl;

P) E is C(R3)(R4)A;

Q) R5 is hydrogen or methyl;

R) R3 is C₁-C₃alkoxy;

S) E is C(R3)(R4)A and A is C(O)OR26; R26 is H or C₁-C₃alkyl;

T) A compound which is selected from the group consisting of:

(2S,1′R)-2-Ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;(2S,1′R)-2-Ethoxy-3-(4-{1′-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-trifluoromethylphenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;

(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(2-ethoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;

(2S,1′R)-2-ethoxy-3-{4-[1′-(3-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;

(2S,1′R)-2-ethoxy-3-{4-[1′-(3-fluoro-5-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;

(2S,1′R)-3-(4-{1′-[(biphenyl-3-ylmethyl)-carbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;

(2S,1R)-3-(4-{1′-[2-(3-chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;

(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(3-fluoro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;

(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(2-fluoro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;

(2S,1′R)-3-(4-{1′-[2-(2,4-dichloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;

(2S,1′R)-3-(4-{1′-[2-(2,6-dichloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;

(2S,1′R)-3-(4-{1′-[2-(2-chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S,1′R)-3-(4-{1′-[2-(4-tert-butyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;

(2S,1′R)-2-ethoxy-3-{4-[1′-(4-fluoro-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;(2S,1′R)-2-ethoxy-3-{4-[1′-(4-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;

(2S,1′R)-3-{4-[1′-(4-tert-butyl-benzylcarbamoyl)-ethoxy]-phenyl}-2-ethoxy-propionicacid; (2S,1′R)-3-{4-[1′-(4-tert-butyl-phenylcarbamoyl)-ethoxy]-phenyl}-2ethoxy-propionicacid;(2S,1′R)-3-{4-[1′-(4-trans-tert-butyl-cyclohexylcarbamoyl)-ethoxy]-phenyl}-2-ethoxy-propionicacid;

(2S)-3-{4-[1-(4-tert-butyl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-2-methoxy-3-(4-{1-methyl-1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;

(2S)-3-(4-{1-[2-(2-ethoxy-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;

2-methoxy-3-(4-{1-methyl-1-[2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;

(2S)-2-methoxy-3-{4-[1-methyl-1-(3-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;(2S)-3-(4-{1-[2-(2-chloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-(4-{1-[(biphenyl-3-ylmethyl)-carbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-(4-{1-[2-(2,5-dimethoxy-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-(4-{1-[2-(2-fluoro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-2-ethoxy-3-(4-{1-methyl-1-[2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;

(2S)-2-ethoxy-3-{4-[1-(3-fluoro-5-trifluoromethyl-benzylcarbamoyl)-1-methyl-ethoxy]-phenyl}-propionicacid;

(2S)-3-(4-{1-[2-(2-chloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S)-3-(4-{1-[(biphenyl-3-ylmethyl)-carbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid;

(2S)-3-(4-{1-[2-(3-chloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid;

(2S)-3-(4-{1-[2-(2,5-dimethoxy-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid;

(2S)-2-ethoxy-3-(4-{1-[2-(2-fluoro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-propionicacid;

(2S)-3-{3-[1-(4-tert-butyl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-3-{3-[1-(3-fluoro-5-trifluoromethyl-benzylcarbamoyl)-1-methyl-ethoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-3-(3-{1-[(biphenyl-3-ylmethyl)-carbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-(3-{1-[2-(3-chloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-2-methoxy-3-{4-[(1-phenyl-ethylcarbamoyl)-methoxy]-phenyl}-propionicacid;

(2S)-3-(3-{1-[2-(2,4-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-(3-{1-[2-(2,6-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-(4-{1-[2-(2,4-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-(4-{1-[2-(2,4-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid;

(2S)-3-(4-{1-[2-(2,6-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid;

(2S)-2-ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-propionicacid;

(2S)-2-ethoxy-3-(4-{1-[2-(2-ethoxy-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-propionicacid;

2-Ethoxy-3-{4-[1-(3-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;

2-Ethoxy-3-{4-[1-(5-fluoro-3-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;

2-Ethoxy-3-{4-[1-(3-phenyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;

2-Ethoxy-3-{4-[1-(4-phenoxy-phenylethylcarbamoyl)-ethoxy]-phenyl}-propionicacid;

2-Ethoxy-3-{4-[1-(3-trifluoromethyl-phenylethylcarbamoyl)-ethoxy]-phenyl}-propionicacid;

3-(4-{1-[2-(2,6-Dichloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;

2-Ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;

2-Ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;

3-(4-{Cyclohexyl-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-2-ethoxy-propionicacid;

2-Ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-2-phenyl-ethoxy}-phenyl)-propionicacid; and

(2S,1′R)-2-ethoxy-3-{4-[1′-(2-thiophen-2-yl-ethylcarbamoyl)-ethoxy]-phenyl}-propionicacid; and pharmaceutically acceptable salts thereof;

U) A compound selected from the group consisting of

(2S,1′R)-3-{4-[1′-(4-tert-butyl-cyclohexylcarbamoyl)-ethoxy]-phenyl}-2-ethoxypropionic acid;

(2S,1′R)-2-ethoxy-3-(4-{1′-[(thiophen-2-ylmethyl)-carbamoyl]-ethoxy}-phenyl)-propionicacid;

(2S,1′R)-2-ethoxy-3-{4-[1′-(2-thiophen-2-yl-ethylcarbamoyl)-ethoxy]-phenyl}-propionicacid; and

pharmaceutically acceptable salts thereof;

V) A compound selected from the group consisting of

(2S,1′R)-2-ethoxy-3-[4-(1′-heptylcarbamoyl-ethoxy)-phenyl]-propionicacid;

(2S)-3-[3-(1-heptylcarbamoyl-1-methyl-ethoxy)-phenyl]-2-methoxy-propionicacid;

(2S)-2-ethoxy-3-[4-(1-heptylcarbamoyl-1-methyl-ethoxy)-phenyl]-propionicacid;

2-Ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-propoxy}-phenyl)-propionicacid;

2-Ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-propoxy}-phenyl)-propionicacid; and

pharmaceutically acceptable salts thereof;

W) A compound selected from the group consisting of

(2S)-3-(4-{2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-(4-{2-[4-(4-chloro-benzoyl)-piperidin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-[4-(2-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-oxo-ethoxy)-phenyl]-2-methoxy-propionicacid;

(2S)-3-(4-{2-[4-(2-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid;

2S)-3-[4-(2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-2-oxo-ethoxy)-phenyl]-2-methoxy-propionicacid;

(2S)-3-(4-{2-[4-(4-acetyl-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-[4-(2-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-2-oxo-ethoxy)-phenyl]-2-methoxy-propionicacid;

(2S)-3-{4-[2-(4-benzhydryl-piperazin-1-yl)-2-oxo-ethoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-3-(4-{2-[4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-{4-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-3-(4-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-2-methoxy-3-4-{[2-(2-methoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionicacid;

(2S)-3-(4-{2-[4-(3-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-(4-{2-[4-(4-chloro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methoxy-propionicacid;2S)-2-methoxy-3-{4-[2-oxo-2-(4-p-tolyl-piperazin-1-yl)-ethoxy]phenyl}-propionicacid;

2S)-2-methoxy-3-(4-{2-oxo-2-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethoxy}-phenyl)-propionicacid; and

a pharmaceutically acceptable salt thereof.

X) A compound selected from the group consisting of(2S)-3-(4-{[benzyl-(1-phenyl-ethyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid

(2S)-3-(4-{[ethyl-(2-fluoro-benzyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-[4-({ethyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-carbamoyl}-methoxy)-phenyl]-2-methoxy-propionicacid;

(2S)-3-(4-{[ethyl-(3-methyl-benzyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-2-methoxy-3-{4-[(methyl-naphthalen-1-ylmethyl-carbamoyl)-methoxy]-phenyl}-propionicacid;

(2S)-3-(4-{[butyl-(1-phenyl-ethyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-(4-{[butyl-(1-phenyl-ethyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-2-methoxy-3-(4-{[methyl-(1-phenyl-ethyl)-carbamoyl]-methoxy}-phenyl)-propionicacid;

(2S)-3-(4-{[benzyl-(2-ethoxycarbonyl-ethyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid; and

pharmaceutically acceptable salts there.

Y) A compound as Claimed by Claim 1 wherein the compound is selectedfrom the group consisting of:

(2S)-3-(4-{[benzyl-(2-ethoxycarbonyl-ethyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid;

S)-3-{4-[(benzyl-phenethyl-carbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-2-methoxy-3-{4-[(1-methoxycarbonyl-2-phenyl-ethylcarbamoyl)-methoxy]-phenyl}-propionicacid;

(2S)-3-(4-{[benzyl-(2-ethoxycarbonyl-ethyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-(4-{[(benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-{4-[(6-fluoro-benzothiazol-2-ylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-2-methoxy-3-{4-[(1-naphthalen-1-yl-ethylcarbamoyl)-methoxy]-phenyl}-propionicacid;

(2S)-2-methoxy-3-(4-{[(naphthalen-1-ylmethyl)-carbamoyl]-methoxy}-phenyl)-propionicacid;

(2S)-3-(4-{[2-(2,6-dichloro-benzylsulfanyl)-ethylcarbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid;

(2S)-3-[4-({[(4-chloro-phenyl)-phenyl-methyl]-carbamoyl}-methoxy)-phenyl]-2-methoxy-propionicacid;

(2S)-3-{4-[(3,3-diphenyl-propylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid;

2-methoxy-2-methyl-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionicacid;

(2S)-2-methoxy-3-(4-{[3-(methyl-phenyl-amino)-propylcarbamoyl]-methoxy}-phenyl)-propionicacid;

(2S)-2-methoxy-3-(4-{[3-(methyl-phenyl-amino)-propylcarbamoyl]-methoxy}-phenyl)-propionicacid;

(2S)-2-methoxy-3-{4-[(1-methoxycarbonyl-2-phenyl-ethylcarbamoyl)-methoxy]-phenyl}-propionicacid;

(2S)-2-methoxy-3-{4-[(2-pyridin-2-yl-ethylcarbamoyl)-methoxy]-phenyl}-propionicacid;

(2S)-E-3-{4-[(4-tert-butyl-cyclohexylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-Z-3-{4-[(4-tert-butyl-cyclohexylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-3-(4-cyclobutylcarbamoylmethoxy-phenyl)-2-methoxy-propionic acid;

(2S)-2-methoxy-3-{4-[(1-methyl-3-phenyl-propylcarbamoyl)-methoxy]-phenyl}-propionicacid;

(2S)-3-{4-[(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-3-{4-[(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-3-{4-[(4-tert-butyl-thiazol-2-ylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid;

3-{4-[(5-cyclopropyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-2-methoxy-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionicacid;

(2S)-3-{4-[(1,3-dimethyl-butylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-2-methoxy-3-{4-[(1-methyl-hexylcarbamoyl)-methoxy]-phenyl}-propionicacid;

(2S)-2-methoxy-3-{4-[(1-methyl-butylcarbamoyl)-methoxy]-phenyl}-propionicacid;

(2S)-2-methoxy-3-{4-[(3-methyl-butylcarbamoyl)-methoxy]-phenyl}-propionicacid;

(2S)-3-{4-[(2,2,3,3,4,4,4-heptafluoro-butylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid;

(2S)-3-(4-cyclopentylcarbamoylmethoxy-phenyl)-2-methoxy-propionic acid;

3-{3-[(4-cis-tert-butyl-cyclohexylcarbamoyl)-methoxy]-phenyl}-2-methoxy-propionicacid; and

pharmaceutically acceptable salts thereof;

Z) A compound

and pharmaceutically acceptable salts thereof;

AA) A compound that is the hemipiperazine salt;

BB) R5 is methyl and R6 is hydrogen;

CC) R1 is hydrogen;

DD) R2 is arylalkyl wherein arylalkyl is unsubstituted or substituedwith from one to three substituents each independently selected from thegroup consisting of R2′;

EE) R2 is arylalkyl;

FF) R2 is arylalkyl and the aryl group is phenyl;

GG) E is C(R3)(R4)A, and R3 is hydrogen and R4 is alkoxy;

HH) R4 is ethoxy;

II) A is COOH;

JJ) R4 is halo, C₁-C₅ alkyl, C₁-C₅ alkoxy, C₃-C₆ cycloalkyl, aryl C₀-C₄alkyl, C₁₋₄alkoxyaryl, and phenyl, wherein said C₁-C₅ alkyl, C₁-C₅alkoxy, C₃-C₆ cycloalkyl, aryl C₀-C₄ alkyl, C₁₋₄alkoxyaryl, and phenyl,are each unsubstituted or each independently substituted with from oneto three groups each independently selected from R4′; or R3 and R4 arecombined to form a C₃-C₆ cycloalkyl;

KK) R4 is selected from the group consisting of C₁-C₅ alkoxy, C₃-C₆cycloalkyl, aryl C₀-C₄ alkyl, C₁₋₄alkoxyaryl, and phenyl, wherein saidC₁-C₅ alkoxy, C₃-C₆ cycloalkyl, aryl C₀-C₄ alkyl, C₁₋₄alkoxyaryl, andphenyl are each unsubstituted or each independently substituted withfrom one to three groups each independently selected from R4′; or R3 andR4 are combined to form a C₃-C₆ cycloalkyl;

LL) R2 is arylC2alkyl;

MM) aryl is phenyl;

NN) A compound of this invention is formulated as a tablet or capsule;

OO) A compound of this invention is used to treat diabetes;

PP) A compound of this invention is used to treat Syndrome X;

QQ) A compound of this invention is used to treat elevated lipids;

RR) A compound of this invention is a pharmaceutically acceptable salt;

In one preferred class of compounds of the invention:

SS) R2 is substituted arylalkyl and R1 is hydrogen;

TT) R2 is aryalklyl, R1 is hydrogen, R5 is hydrogen, E is C(R3)(R4)A,and A is COOR14, said arylalkyl is unsubstituted or substituted with afrom one to three substituents each independently selected from thegroup consisting of R2′;

UU) R2 is arylaklyl, R1 is hydrogen, R5 is hydrogen, E is C(R3)(R4)A, R4is C1-C3alkoxy, and A is COOR14, said arylalkyl is unsubstituted orsubstituted with a from one to three substituents each independentlyselected from the group consisting of R2′

VV) R2 is arylC₁-C₃alkyl, R1 is hydrogen, R5 is hydrogen, E isC(R3)(R4)A, R4 is C1-C3alkoxy, and A is COOR14, said arylalkyl isunsubstituted or substituted with a from one to three substituents eachindependently selected from the group consisting of R2′;

WW) R2 is substituted arylC₁-C₃alkyl wherein the substitution is from1-2 each independently selected from the group consisting of C₁-C₃alkyl, halo, and C₁-C₃alkoxy, R1 is hydrogen, R5 is hydrogen, E isC(R3)(R4)A, R4 is C₁-C₃alkoxy, and A is COOR14;

XX) R2 is substituted arylC₁-C₃alkyl wherein the substitution is from1-2 each independently selected from the group consisting of C₁-C₃ alkyland C₁-C₃alkoxy, R1 is hydrogen, R5 is hydrogen, E is C(R3)(R4)A, R4 isC₁-C₃alkoxy, and A is COOR14;

YY) R1 is selected from the group consisting of hydrogen, C1-C4 alkyl,and arylC0-C4alkyl, R2 is arylC0-C4alkyl, heteroarylC0-C4alkyl;

ZZ) R2 is arylC0-C4 alkyl, C1-C8 alkyl, heteroarylC0-C4alkyl,C3-C6cycloalkyl, C0-C4alkylC(O)heteroC1-C8alkyl, arylheteroC1-C8alkyl,wherein the arylC0-C4 alkyl, C1-C8 alkyl, heteroarylC0-C4alkyl,C3-C6cycloalkyl, C0-C4alkylC(O)heteroC1-C8alkyl, arylheteroC1-C8alkylare each independently unsubstituted or each independently substitutedwith from one to three substituents each independently selected from thegroup consisting of phenyl, halophenyl, phenoxy, halo, haloC1-C4alkyl,C1-C4alkoxy, and C3-C6cyclalkyl;

AAA) R1 and R2 together form a piperidine, a piperazine or adihydroisoquinoline group which piperidine, a piperazine or adihydroisoquinoline are each independently unsubstituted or eachindependently subtituted with from one to three substituents selectedfrom the group consisting of C1-C4 alkyl, phenyl, halophenyl,trifluormethylphenyl, methylphenyl, methoxyphenyl, acetylphenyl, benzyl,halobenzyl, benzoyl, halobenzoyl, trifluormethylbenzoyl, methylbenzoyl,methoxybenzoyl, acetyl benzoyl, biphenylmethylene,(pheny)(halophenyl)methylene, and bihalophenylmethylene.

EQUIVALENTS

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A Compound of the structural formula I: Formula I

(a) R1 is hydrogen, (b) R2′ is selected from a group consisting of C₁-C₅alkyl, C₃-C₆ cycloalkyl, C₁-C₅alkoxy, arylC₀-C₂alkoxy, haloC₁-C₃alkyl,halo, aryl, —C(O)C₁-C₅alkyl, —C(O)-aryl, haloC₁-C₅alkyloxy,arylC₁-C₅alkyl, and biarylC₁-C₅alkyl; and which —C(O)-aryl isunsubstituted or substituted with from one to three substituents eachindependently selected from the group consisting of halo, C₁-C₅ alkyl,haloC₁-C₅ alkyl, C₁-C₅ alkoxy, and —C(O)C₁-C₅alkyl; and which C₁-C₅alkyl, arylC₁-C₅alkyl, biarylC₁-C₅alkyl, and aryl are each independentlyunsubstituted or substituted with from one to three substituents eachindependently selected from the group consisting of halo, C₁-C₅alkyl,aryl, haloC₁-C₅ alkyl, trihaloC₁-C₃alkyl, C₁-C₅alkoxy, andarylC₁-C₅alkyl; and which aryl is unsubstituted or substituted with fromone to three substituents each independently selected from the groupconsisting of halo, C₁-C₈alkyl, aryl, haloC₁-C₅alkyl, trihaloC₁-C₃alkyl,C₁-C₅alkoxy, and arylC₁-C₅alkyl; (c) R2 is selected from the groupconsisting of C₁-C₈ alkyl, C₃-C₆ cycloalkyl, aryl-C₀₋₄-alkyl,aminoC₁-C₄alkyl, C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, arylheteroC₁-C₈alkyl,C₀₋₄-alkyl-C(O)heteroC₄-C₈alkyl, —CH(C(O)OCH₃)benzyl, and—CH₂—C(O)—R15″-R16″, and which C₁-C₈ alkyl, C₃-C₆ cycloalkyl,aryl-C₀₋₄-alkyl, aminoC₁-C₄alkyl, C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl,arylheteroC₁-C₈alkyl, C₀₋₄-alkyl-C(O)heteroC₁-C₈alkyl, and—CH₂—C(O)—R15″-R16″ are each independently unsubstituted or substitutedwith from one to three substituents each independently selected from thegroup consisting of R2′; (d) R15″ is O or NH; (e) R16″ is C₁-C₂ alkyl orbenzyl which C₁-C₂ alkyl and benzyl are each unsubstituted orsubstituted with from one to three substituents each independentlyselected from the group consisting of R16′; (f) R7′ and R7″ are eachindependently selected from the group consisting of C₁-C₄alkyl and C₁-C₄haloalkyl; (g) n and m are each independently selected from the groupconsisting of 0, 1, 2 and 3; (h) A is selected from the group consistingof (CH₂)_(m) COOR14, C₁-C₃alkylnitrile, carboxamide, sulfonamide,acylsulfonamide and tetrazole, and which sulfonamide, acylsulfonamideand tetrazole are each independently unsubstituted or substituted withfrom one to three substituents each independently selected from thegroup consisting of A′; (i) A′ is a group consisting of C₁-C₄alkyl,C₁-C₄ haloalkyl, heteroaryl, and aryl, and wherein heteroaryl and arylare each independently unsubstituted or substituted with from one tothree substituents each independently selected from the group consistingof halo, C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, and —C(O)C₁-C₅alkyl; (j) R3 is selected from the group consisting of H, C₁-C₅ alkyl,C₁-C₅ alkenyl, and C₁-C₆ alkoxy; (k) R4 is selected from the groupconsisting of H, halo, C₁-C₅ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, arylC₀-C₄ alkyl, and C₀₋₄alkoxyaryl, and which C₁-C₅ alkyl, C₁-C₅ alkoxy,C₃-C₆ cycloalkyl, aryl C₀-C₄ alkyl, and C₀₋₄alkoxyaryl are eachindependently unsubstituted or each independently substituted with fromone to four substituents each independently selected from R4′; or R3 andR4 are combined to form a C₃-C₆ cycloalkyl; (l) R5 and R6 are eachindependently selected from the group consisting of hydrogen, C₁-C₈alkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, C₃-C₆cycloalkylaryl-C₀₋₂-alkyl, C₃-C₆ cycloalkyl-C₀₋₂-alkyl, and—CH₂—C(O)—R17-R18, and which C₁-C₈ alkyl, aryl-C₀₋₄-alkyl,heteroaryl-C₀₋₄-alkyl, C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, C₃-C₆cycloalkyl-C₀₋₂-alkyl, and —CH₂—C(O)—R17-R18 are each independentlyunsubstituted or substituted with from one to four substituents eachindependently selected from the group consisting of R5′; (m) R4′, R5′,and R13″ are each independently a group consisting of C1-C5 alkyl, C1-C5alkoxy, C1-C5 haloalkyl, C1-C5 haloalkoxy, nitro, cyano, CHO, hydroxy,C₁-C₄ alkanoic acid, phenyl, aryloxy, SO₂R7′, SR7″, arylC₀-C₂alkoxy,C1-C6alkylcarboxamido, and COOH; (n) R16′ is a group consisting of halo,C₁-C₈alkyl, aryl, haloalkyl, trihaloC₁-C₃alkyl, C₁-C₅alkoxy, andarylC₁-C₅alkyl; (o) R17 and R18 are each independently selected fromC₁-C₈ alkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, C₃-C₆cycloalkylaryl-C₀₋₂-alkyl, and C₃-C₆ cycloalkyl-C₀₋₂-alkyl; (p) R14 isselected from the group consisting of hydrogen, C1-C4alkyl, aryl, andarylmethyl, and which C1-C4alkyl are each independently unsubstituted orindependently substituted with from one to three substituents eachindependently selected from the group consisting of R13′ and whicharylmethyl and aryl are each independently unsubstituted orindependently substituted with from one to three substituents eachindependently selected from the group consisting of R14′; (q) R13′ is agroup consisting of C₁-C₅ alkyl, C₃-C₆ cycloalkyl, C₁-C₅ haloalkyl,C₁-C₅ alkoxy, aryloxy, halo, aryl, —C(O)C₁-C₅alkyl, —C(O)-aryl,haloC₁-C₅alkyloxy, arylC₁-C₅ alkyl, and C₁-C₅ alkylbiaryl, and which—C(O)aryl, aryl, arylC₁-C₅ alkyl, and C₁-C₅ alkylbiaryl are eachindependently unsubstituted or substutited with from one to threesubstituents each independently selected from the group consisting ofR13″; and (r) R14′ is a group consisting of halo, C1-C8alkyl, C₁-C₅haloalkyl, C₁-C₅ alkoxy, and arylC₀-C₄alkyl; or (s) a pharmaceuticallyacceptable salt thereof.
 2. A compound as claimed by claim 1 of thestructural Formula II:

wherein R19 is selected from the group consisting of hydrogen,C1-C4alkyl, aryl, and arylmethyl, wherein the alkyl, aryl and arylmethylare each unsubstituted or substituted with from one to threesubstituents each independently selected from R14′.
 3. A compound asclaimed by claim 2 that is of the following structural formula III:

wherein R19 is selected from the group consisting of hydrogen,C1-C4alkyl, aryl, and arylmethyl, wherein the alkyl, aryl and arylmethylare each unsubstituted or substituted with from one to threesubstituents each independently selected from R14′.
 4. A compound asclaimed by claim 1 wherein R1 is hydrogen.
 5. A compound as claimed byof claim 4 wherein R2 is selected from the group consisting ofarylC₀-C₄alkyl, C₁-C₈ alkyl, heteroarylC₀-C₄alkyl, C₃-C₆ cycloalkyl,C₀-C₄alkyl-C(O)-heteroC₁-C₈ alkyl, arylheteroC₁-C₈alkyl, wherein each ofsaid R2 is unsubstituted or substituted by one or two substituents eachindependently selected from the group consisting of phenyl, halophenyl,phenoxy, halo, haloC₁-C₄ alkyl, C₁-C₄alkoxy, and C₃-C₆ cycloalkyl.
 6. Acompound as claimed by claim 5 wherein R2 is arylC₀-C₄alkyl wherein thearyl is phenyl or napthyl, and the C₀-C₄alkyl is selected from the groupconsisting of methyl, ethyl and not present, that is C₀ alkyl.
 7. Acompound as claimed by of claim 5 wherein the R2 group is substitutedwith one or two substituents each independently selected from the groupconsisting of methyl, ethyl, t-butyl, fluorine, chlorine, bromine,trifluoromethyl, methoxyl, ethoxyl, phenyl, and phenoxyl.
 8. A compoundas claimed by claim 1 wherein R2 is —CH(C(O)OCH₃)benzyl.
 9. A compoundas claimed by claim 1 or claim 4 wherein R6 is selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, and aryl-C₀₋₄-alkyl, wherein thealkyl and arylalkyl are each independently substituted with from one tothree substituents each independently selected from the group consistingof R5′.
 10. A compound as claimed by claim 9 wherein R5 is H or methyl.11. A compound as claimed by any one of claims 1 or claim 10 wherein R6is C₁-C₃ alkyl.
 12. A compound as claimed by claim 11, wherein R6 ismethyl.
 13. A compound as claimed by claim 1 wherein R5 is hydrogen ormethyl, R6 is C₁-C₃ alkyl, and R3 is C₁-C₃alkoxy.
 14. A compound asclaimed by claim 1 wherein A is C(O)OR26; R26 is H or C₁-C₃alkyl.
 15. Acompound as claimed by claim 1 which is selected from the groupconsisting of:(2S,1′R)-2-Ethoxy-3-(4-{1′-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;(2S,1′R)-2-Ethoxy-3-(4-{1′-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(4-trifluoromethyl-phenyl-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(2-ethoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;(2S,1′R)-2-ethoxy-3-{4-[1′-(3-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;(2S,1′R)-2-ethoxy-3-{4-[1′-(3-fluoro-5-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;(2S,1′R)-3-(4-{1′-[(biphenyl-3-ylmethyl)-carbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S,1′R)-3-(4-{1′-[2-(3-chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(3-fluoro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;(2S,1′R)-2-ethoxy-3-(4-{1′-[2-(2-fluoro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;(2S,1′R)-3-(4-{1′-[2-(2,4-dichloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S,1′R)-3-(4-{1′-[2-(2,6-dichloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S,1′R)-3-(4-{1′-[2-(2-chloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S,1′R)-3-(4-{1′-[2-(4-tert-butyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S,1′R)-2-ethoxy-3-{4-[1′-(4-fluoro-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;(2S,1′R)-2-ethoxy-3-{4-[1′-(4-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;(2S,1′R)-3-{4-[1′-(4-tert-butyl-benzylcarbamoyl)-ethoxy]-phenyl}-2-ethoxy-propionicacid;(2S,1′R)-3-{4-[1′-(4-tert-butyl-phenylcarbamoyl)-ethoxy]-phenyl}-2-ethoxy-propionicacid;(2S,1′R)-3-{4-[1′-(4-trans-tert-butyl-cyclohexylcarbamoyl)-ethoxy]-phenyl}-2-ethoxy-propionicacid;(2S)-3-{4-[1-(4-tert-butyl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-2-methoxy-propionicacid;(2S)-2-methoxy-3-(4-{1-methyl-1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;(2S)-3-(4-{1-[2-(2-ethoxy-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;2-methoxy-3-(4-{1-methyl-1-[2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;(2S)-2-methoxy-3-{4-[1-methyl-1-(3-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;(2S)-3-(4-{1-[2-(2-chloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;(2S)-3-(4-{1-[(biphenyl-3-ylmethyl)-carbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;(2S)-3-(4-{1-[2-(2,5-dimethoxy-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;(2S)-3-(4-{1-[2-(2-fluoro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;(2S)-2-ethoxy-3-(4-{1-methyl-1-[2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;(2S)-2-ethoxy-3-{4-[1-(3-fluoro-5-trifluoromethyl-benzylcarbamoyl)-1-methyl-ethoxy]-phenyl}-propionicacid;(2S)-3-(4-{1-[2-(2-chloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S)-3-(4-{1-[(biphenyl-3-ylmethyl)-carbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S)-3-(4-{1-[2-(3-chloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S)-3-(4-{1-[2-(2,5-dimethoxy-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S)-2-ethoxy-3-(4-{1-[2-(2-fluoro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-propionicacid;(2S)-3-{3-[1-(4-tert-butyl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-2-methoxy-propionicacid;(2S)-3-{3-[1-(3-fluoro-5-trifluoromethyl-benzylcarbamoyl)-1-methyl-ethoxy]-phenyl}-2-methoxy-propionicacid;(2S)-3-(3-{1-[(biphenyl-3-ylmethyl)-carbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;(2S)-3-(3-{1-[2-(3-chloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;(2S)-2-methoxy-3-{4-[(1-phenyl-ethylcarbamoyl)-methoxy]-phenyl}-propionicacid;(2S)-3-(3-{1-[2-(2,4-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;(2S)-3-(3-{1-[2-(2,6-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;(2S)-3-(4-{1-[2-(2,4-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-methoxy-propionicacid;(2S)-3-(4-{1-[2-(2,4-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S)-3-(4-{1-[2-(2,6-dichloro-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-2-ethoxy-propionicacid;(2S)-2-ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-propionicacid;(2S)-2-ethoxy-3-(4-{1-[2-(2-ethoxy-phenyl)-ethylcarbamoyl]-1-methyl-ethoxy}-phenyl)-propionicacid;2-Ethoxy-3-{4-[1-(3-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;2-Ethoxy-3-{4-[1-(5-fluoro-3-trifluoromethyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;2-Ethoxy-3-{4-[1-(3-phenyl-benzylcarbamoyl)-ethoxy]-phenyl}-propionicacid;2-Ethoxy-3-{4-[1-(4-phenoxy-phenylethylcarbamoyl)-ethoxy]-phenyl}-propionicacid;2-Ethoxy-3-{4-[1-(3-trifluoromethyl-phenylethylcarbamoyl)-ethoxy]-phenyl}-propionicacid;3-(4-{1-[2-(2,6-Dichloro-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-2-ethoxy-propionicacid;2-Ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;2-Ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionicacid;3-(4-{Cyclohexyl-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-2-ethoxy-propionicacid; and2-Ethoxy-3-(4-{1-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-2-phenyl-ethoxy}-phenyl)-propionicacid; or pharmaceutically acceptable salts thereof.
 16. A compound asclaimed by claim 1 wherein the compound is selected from the groupconsisting of(2S,1′R)-3-{4-[1′-(4-tert-butyl-cyclohexylcarbamoyl)-ethoxy]-phenyl}-2-ethoxy-propionicacid; or pharmaceutically acceptable salts thereof.
 17. A compound asclaimed by claim 1 wherein the compound is

or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atleast one compound as claimed by claim 1 or a pharmaceuticallyacceptable salt thereof.
 19. A method of treating diabetes mellitus in amammal, comprising the step of administering to the mammal atherapeutically effective amount of at least one compound of claim 1 ora pharmaceutically acceptable salt thereof.
 20. A method of treatingSyndrome X in a mammal, comprising the step of administering to themammal a therapeutically effective amount of at least one compound ofclaim 1 or a pharmaceutically acceptable salt thereof.
 21. A compound orpharmaceutically acceptable salt thereof according to claim 1 for use asa medicine.
 22. A compound of the formula

or a pharmaceutically acceptably salt thereof.
 23. A compound as claimedby claim 1 that is of the formula:

or a pharmaceutically acceptable salt thereof.
 24. A compound as claimedby any one of claims 1, or 23 wherein the compound is a pharmaceuticallyacceptable salt.
 25. A compound of claim 1 that is(2S)-3-(4-{[2-(2,6-dichloro-benzylsulfanyl)-ethylcarbamoyl]-methoxy}-phenyl)-2-methoxy-propionicacid.
 26. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and at least one compound as claimed by claim 23 or24.